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Electrophysiological Predictors of Transplantation and Left Ventricular Assist Device-Free Survival in Patients With Nonischemic Cardiomyopathy Undergoing Ventricular Tachycardia Ablation
JACC: CLINICAL ELECTROPHYSIOLOGY
VOL. 1, NO. 5, 2015
ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 2405-500X/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jacep.2015.07.005
Electrophysiological Predictors of Transplantation and Left Ventricular Assist Device-Free Survival in Patients With Nonischemic Cardiomyopathy Undergoing Ventricular Tachycardia Ablation David S. Frankel, MD, Jackson J. Liang, DO, Gregory Supple, MD, Sanjay Dixit, MD, Mathew D. Hutchinson, MD, Melissa A. Elafros, PHD, David J. Callans, MD, Francis E. Marchlinski, MD
ABSTRACT OBJECTIVES This study sought to identify predictors of transplantation/left ventricular assist device (LVAD)-free survival among patients with left ventricular nonischemic cardiomyopathy (NICM) and ventricular tachycardia (VT). BACKGROUND Outcomes vary widely among these patients. METHODS The derivation cohort consisted of patients with NICM undergoing VT ablation from 2007 to 2011. Scar percentage was defined as the area of low voltage divided by total surface area. Cox proportional hazard modeling was performed to identify predictors of shorter time to the primary endpoint of death, transplantation, or LVAD. A risk score was created using b regression coefficients. The risk score was then validated in a separate cohort of patients undergoing ablation from 2004 to 2007. RESULTS Of 100 patients with NICM undergoing VT ablation, 41 experienced an endpoint during 1.2 years mean follow-up. In multivariate modeling, VT storm, wider native QRS duration, greater endocardial/epicardial bipolar scar percentage, and lower left ventricular ejection fraction (LVEF) identified worse transplantation/LVAD-free survival. The risk score ¼ (VT storm 83) þ (greater of endocardial/epicardial bipolar scar percentage 4) þ (QRS duration) (LVEF 3). A score >180 identified patients at high risk for the endpoint, whereas a score <100 identified low risk. Among the 50-patient validation cohort, the high-risk group again had worse transplantation/LVAD-free survival during a mean 3.0 years of follow-up (<10% vs. 50% for intermediate and >80% for low, p < 0.001). CONCLUSIONS Wider native QRS duration, greater bipolar scar percentage, VT storm, and lower LVEF are potent predictors of time to death, transplantation, or LVAD. By combining these variables into an “electrophysiological risk score,” patient risk can be refined. (J Am Coll Cardiol EP 2015;1:398–407) © 2015 by the American College of Cardiology Foundation.
T Listen to this manuscript’s audio summary by JACC:
he incidence of death, heart transplantation,
prognostic information and potentially guide more
or left ventricular assist device (LVAD) im-
intensive heart failure therapies.
plantation among patients with nonischemic
Greater extent of myocardial delayed enhancement
cardiomyopathy (NICM) presenting with ventricular
on cardiac magnetic resonance imaging (MRI) was
tachycardia (VT) is substantial (1,2). The ability to
recently shown to predict worse outcomes in patients
better risk stratify these patients beyond left ventric-
with NICM (3); however, this finding has yet to
ular ejection fraction (LVEF) could provide valuable
be replicated with other scar assessment modalities.
Clinical Electrophysiology Editor-in-Chief Dr. David J. Wilber. From the Cardiovascular Division, Electrophysiology Section, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania. Supported in part by the F. Harlan Batrus Research Fund and the Susan and Murray Bloom Fund. Dr. Marchlinski has served on scientific advisory boards and received research support from St. Jude Medical and Biosense Webster. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received April 13, 2015; revised manuscript received July 14, 2015, accepted July 16, 2015.
Frankel et al.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 1, NO. 5, 2015 OCTOBER 2015:398–407
399
Wider QRS/Larger Scar Predict Worse NICM Survival
Similarly, wider QRS duration has been inconsistently
present, QRS duration comparisons were
ABBREVIATIONS
related to mortality in patients with NICM (4,5). We
further stratified by QRS morphology category
AND ACRONYMS
hypothesized that larger areas of scar defined by low
(left bundle branch block, right bundle branch
voltage during electroanatomic mapping and wider
block, biventricular paced, right ventricular
QRS durations would predict worse transplantation-
paced). Left bundle branch block, right bundle
and LVAD-free survival among patients with NICM
branch block, and intraventricular conduction
and VT. We further sought to develop and then vali-
delay were defined according to standard
date an electrophysiological risk score to aid in risk
ECG criteria established by the American
stratifying patients with NICM and VT.
Heart Association, the American College of
SEE PAGE 408
METHODS STUDY POPULATION. The risk score was derived
from consecutive patients with left ventricular NICM and sustained VT who had been referred to the Hospital of the University of Pennsylvania for ablation between July 2007 and April 2011. Patients with idiopathic VT, right ventricular cardiomyopathy, or ischemic cardiomyopathy, as defined by history of myocardial infarction or obstructive coronary artery disease on angiography, were excluded. Patients undergoing multiple ablation procedures during this period were included once, with analysis of the voltage maps from the first procedure only. However, if epicardial mapping was not performed during the first procedure but was performed during a subsequent procedure, the subsequent epicardial map was analyzed. The risk score was validated in a separate cohort of consecutive patients with identical inclusion and exclusion criteria who had been referred to our institution for ablation between March 2004 and June 2007. VT storm was defined as 3 or more separate episodes of VT within 24 h. All patients provided written informed consent for catheter ablation and for their anonymized medical information to be included in research studies. MEASUREMENT OF QRS DURATION AND CLASSIFICATION
ECG = electrocardiogram LVAD = left ventricular assist device
LVEF = left ventricular ejection fraction
MRI = magnetic resonance imaging
Cardiology, and the Heart Rhythm Society (6).
NICM = nonischemic
ECGs were analyzed blinded to patient
cardiomyopathy
outcome.
VT = ventricular tachycardia
ELECTROANATOMIC MAPPING AND VT ABLATION. Electro-
anatomic mapping (CARTO, Biosense Webster, Diamond Bar, California) was performed during sinus or paced rhythm to define areas of low voltage and abnormal electrograms, consistent with scar (7), using a 3.5-mm open irrigation tip catheter (Navistar Thermocool, Biosense Webster) maintaining a fill threshold of 15 mm to ensure adequate sampling of the entire represented surface area. Bipolar electrograms were recorded between the distal and ring electrodes of the mapping catheter and filtered at 30 to 400 Hz. Endocardial unipolar electrograms were recorded between the distal electrode of the mapping catheter and Wilson’s central terminal and filtered at 1 to 240 Hz (8). All patients underwent endocardial mapping; epicardial mapping was performed when an ECG of spontaneous or induced VT suggested an epicardial exit (9) and/or endocardial ablation failed to eliminate targeted VT. Voltage maps were analyzed off-line using the CARTO area measurement software, with endocardial bipolar low voltage defined as <1.5 mV, endocardial unipolar as <8.3 mV, and epicardial bipolar as <1.0 mV (10,11). To avoid misclassification of epicardial fat or coronary arteries as scar, areas of epicardial bipolar voltage <1.0 mV were only considered scar if wide,
OF QRS MORPHOLOGY. The presenting QRS duration,
split, or late electrograms were also present (12). Scar
whether paced or conducted, was measured using
percentage was defined as the area of low voltage
digital calipers on the 12-lead electrocardiogram (ECG)
divided by the entire surface area of the mapped
immediately preceding VT ablation. For patients pre-
chamber, multiplied by 100. Because some patients
senting in VT, QRS duration was measured on a prior
did not undergo epicardial mapping and to account
ECG or the recordings from the VT ablation (CardioLab,
for the fact that some patients have greater endocar-
GE Medical Systems, Waukesha, Wisconsin) not during
dial bipolar scar percentage whereas others have
VT. For patients presenting in paced rhythm, prior
greater epicardial bipolar scar percentage, a single
ECGs/ablation recordings were similarly searched to
combined
identify and measure native QRS complexes. QRS du-
epicardial bipolar scar percentage,” was created to
rations were compared between those experiencing
most accurately reflect total scar burden. Voltage
death, transplantation, or LVAD and those not expe-
maps were analyzed blinded to patient outcome.
riencing the primary endpoint. Because QRS durations
After
variable,
“greater
of
endocardial
or
electroanatomic mapping, VT induction
would be expected to vary widely on the basis of
was performed. Programmed stimulation was deli-
whether bundle branch block or paced rhythm were
vered from the right and left ventricles, with up to
400
Frankel et al.
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Wider QRS/Larger Scar Predict Worse NICM Survival
3 extrastimuli delivered to refractoriness. When a
30 ms of stored electrograms from spontaneous VT
12-lead ECG of spontaneous VT was available, clinical
episodes. Every spontaneously occurring VT was
VT was defined by match in all 12 leads. When a
considered clinical; thus, a single patient could have
12-lead ECG of spontaneous VT was not available,
multiple clinical VTs. Special attention was paid to
clinical VT was defined by match in near-field and
elimination of clinical VT. Additionally, all mappable
far-field implantable cardioverter-defibrillator elec-
VT and VT with cycle length >250 ms were also
trogram morphology, as well as cycle length within
considered relevant and routinely targeted for ablation. When hemodynamically tolerated, entrainment mapping was used to define critical components of
T A B L E 1 Baseline Characteristics of Derivation Cohort According to Whether Death,
the VT circuit. If VT was not mappable, substrate modification was performed with linear and/or cluster
Transplant, or LVAD Occurred During Follow-Up
lesions targeting exit sites identified by pace-mapping
Death, Transplantation, or LVAD
as well as late potentials. Ablation settings included
Yes (n ¼ 41)
No (n ¼ 59)
p Value
Male, %
90.2
83.1
0.40
grammed stimulation was repeated in patients who
Age, yrs
65.8 11.9
59.2 12.7
0.01
8.9 7.2
7.2 6.3
were medically stable, with up to 3 ventricular extra-
0.20
23.4 12.0
35.4 16.0
<0.001
12 to 15 ohm impedance drop. After ablation, pro-
Baseline characteristics
Years since diagnosis of nonischemic cardiomyopathy Left ventricular ejection fraction, %
power up to 50 W, with temperature limit 42 and goal
stimuli delivered from 2 sites at 2 pacing cycle lengths. Acute procedural success was defined as elimination of all VT. Partial success was defined as elimination of all
NYHA heart failure class
0.02
Class I
29.3
57.6
Class II
48.8
33.9
Class III
17.1
8.5
Class IV
4.9
0.0
clinical VT. Failure was defined as persistent inducibility of clinical VT. CLINICAL FOLLOW-UP. The primary endpoint was
defined as death, heart transplantation, or LVAD
1.6 0.6
1.2 0.3
<0.001
Diabetes, %
26.8
16.9
0.30
Hypertension, %
63.4
55.9
0.90
4.9
5.1
0.90
tervals. Defibrillators were interrogated at each visit
Creatinine, mg/dl
Chronic obstructive pulmonary disease, %
implantation. Patients were routinely evaluated at 6 weeks after ablation and then at 3- to 6-month in-
Thyroid disease, %
34.1
27.1
0.50
to assess for VT recurrence. For patients not followed
Implantable cardioverter defibrillator present, %
97.6
93.2
0.70
at our institution, referring cardiologists were con-
Cardiac resynchronization therapy device present, %
65.9
25.4
<0.001
Ventricular tachycardia storm, %
63.4
42.1
0.04
4.0 1.6
3.0 1.7
0.006
9.8
8.5
1.00
Beta-blocker, %
95.1
83.1
0.10
categorical variables are expressed as percentages.
ACE inhibitor or angiotensin receptor blocker, %
75.6
78.0
0.80
The independent samples Student t test and Pear-
Diuretic, %
85.4
59.3
0.01
son chi-square test were used to compare normally
Amiodarone, %
78.0
52.5
0.01
distributed continuous and dichotomous variables,
Presenting QRS duration (including paced), ms
173.4 37.1
137.6 36.1
<0.001
Native QRS duration, ms
151.7 38.2
128.9 31.5
0.002
Left bundle branch block, %
41.7
17.9
0.01
Right bundle branch block, %
16.7
19.6
0.80
were followed until death, transplantation, LVAD, or
Endocardial bipolar scar, %
16.7 12.8
8.7 8.6
0.001
predictors of time to the primary endpoint using Cox
Endocardial unipolar low voltage, %
54.4 30.3
28.8 21.4
<0.001
proportional hazard modeling. Variables subjected
56.1
59.3
0.90
to univariate screening included age, LVEF, New
18.4 12.3
10.9 8.7
0.001
York Heart Association (NYHA) heart failure class,
Number of ventricular tachycardias occurring spontaneously or induced Atrial fibrillation present on admission, %
social security death index was also queried. STATISTICAL ANALYSIS, DERIVATION OF RISK SCORE, AND VALIDATION OF RISK SCORE. Continuous variables
respectively. The Fisher exact test was used to compare
QRS complex
dichotomous variables with expected cell values <5. The Mann-Whitney U test was used to compare nonnormally distributed continuous variables. Patients the most recent clinical evaluation. We identified
Voltage mapping
Bipolar scar percentage, greater of endocardial or epicardial
patients or family members every 6 to 12 months. The
are expressed as means with standard deviations, and
Baseline medications
Epicardial mapping, %
tacted and telephone interviews performed with
creatinine, VT storm, number of spontaneous and Values are % or mean SD.
induced VTs, acute procedural success, diuretic use,
ACE ¼ angiotensin-converting enzyme; LVAD ¼ left ventricular assist device; NYHA ¼ New York Heart Association.
amiodarone use, endocardial unipolar low voltage percentage, greater of endocardial or epicardial
Frankel et al.
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Wider QRS/Larger Scar Predict Worse NICM Survival
bipolar scar percentage, and native QRS duration. The
low-risk groups using the cutoffs established in the
assumption of proportional hazards was tested and
derivation cohort. Again, Kaplan-Meier curves were
confirmed. Patients without natively conducted QRS
constructed and transplantation/LVAD-free survival
complexes were excluded from QRS duration survival
compared between the risk groups using a log-rank
analysis. Variables showing marginal associations with
test. A receiver operating characteristic curve was
time to death, transplantation, or LVAD on univariate
plotted for the risk score to assess sensitivity and
testing (p < 0.10) were assessed in a multivariate
specificity for 3-year outcomes. Analyses were per-
model.
formed using SPSS (version 20.0, SPSS Inc., Chicago,
Variables retaining significant, independent asso-
Illinois) and R (Foundation for Statistical Computing,
ciations with time to death, transplantation, or LVAD
Vienna, Austria). We considered p values #0.05 to
on multivariate testing were included in the risk score.
indicate statistical significance.
These variables were assigned weighted points in proportion to their b regression coefficient values,
RESULTS
rounded to the nearest integer. By adding these points, an overall risk score was calculated. Cutoffs were
BASELINE CHARACTERISTICS AND OUTCOMES OF
established to divide the population into equally sized
DERIVATION COHORT. Of 100 patients with NICM
high-, intermediate-, and low-risk groups. We then
undergoing VT ablation, 49 recurred over a mean
constructed Kaplan-Meier curves to illustrate trans-
follow-up of 1.2 years (range 3 days to 4.8 years).
plantation and LVAD-free survival and compared
Among these 49, recurrent VT was treated exclusively
the high-, intermediate-, and low-risk groups using a
with antitachycardia pacing in 44% and with at least 1
log-rank test.
implantable cardioverter-defibrillator shock in 56%.
Next, we validated the risk score in a separate pop-
Forty-one patients experienced the primary study
ulation with NICM and VT. Risk scores were calculated
endpoint (3 LVADs, 12 transplantations, and 29
and subjects assigned to high-, intermediate-, and
deaths). Two patients underwent LVAD implantation
F I G U R E 1 QRS Morphology Categories
Presenting and underlying QRS morphologies are illustrated. The number of patients experiencing and not experiencing the primary endpoint (death, transplantation, or LVAD) is provided within each QRS morphology category. Patients who experienced an endpoint were more likely to present with biventricular pacing (p < 0.001) and to have underlying left bundle branch block (p ¼ 0.01). BiV ¼ biventricular; IVCD ¼ intraventricular conduction delay; LBBB ¼ left bundle branch block; LVAD ¼ left ventricular assist device; RBBB ¼ right bundle branch block; RV ¼ right ventricular.
401
402
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Wider QRS/Larger Scar Predict Worse NICM Survival
followed by transplantation. One patient underwent
endpoint were older at the time of presentation, with
LVAD implantation and later died. The majority of
lower LVEF, higher NYHA heart failure class, higher
LVAD implantations and transplantations were per-
creatinine, more likely to present in VT storm, with a
formed for end-stage heart failure; 3 were performed
greater number of VTs occurring spontaneously or
for refractory ventricular arrhythmias. Compared
induced, more likely to have a cardiac resynchroni-
with those who survived the study period without
zation therapy device, and more likely to be taking a
transplantation or LVAD, those who experienced an
diuretic or amiodarone (Table 1).
F I G U R E 2 Distribution of QRS Durations Based on Whether Death, Transplantation, or LVAD Occurred, Stratified by QRS Morphology
Box plots illustrate the distribution of QRS durations among the 2 groups. The box represents the interquartile range; the vertical lines, the maximum and minimum values; and the horizontal line, the median. The number of patients in each category is provided next to that box. (A) Compares all native QRS durations. (B) Compares only normal and intraventricular conduction delay morphologies. (C) Compares only left bundle branch block morphologies. (D) Compares only right bundle branch block morphologies. (E) Compares only biventricular paced morphologies. (F) Compares only right ventricular paced morphologies. Abbreviations as in Figure 1.
Frankel et al.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 1, NO. 5, 2015 OCTOBER 2015:398–407
F I G U R E 3 Distribution of Greater of Endocardial or
Epicardial Bipolar Scar Percentage Based on Whether Death, Transplant, or LVAD Occurred
Wider QRS/Larger Scar Predict Worse NICM Survival
the endpoint in each additional QRS morphology category (left bundle branch block, right bundle branch block, biventricular paced, and right ventricular paced, p ¼ 0.2, 0.7, 0.2, and 0.2, respectively) (Figures 2C to 2F). VOLTAGE MAPPING AND ABLATION. A mean of 357
points were sampled per endocardial voltage map and 506 points per epicardial voltage map. Patients who went on to experience the endpoint had a greater percentage of endocardial bipolar scar (16.7 12.8 vs. 8.7 8.6, p ¼ 0.001) (Table 1), endocardial unipolar low voltage area (54.4 30.3 vs. 28.8 21.4, p < 0.001), and greater of endocardial or epicardial bipolar scar (18.4 12.3 vs. 10.9 8.7, p ¼ 0.001) (Figure 3). Programmed stimulation was performed at the end of ablation in 80% of patients. Among these Box plots illustrate the distribution of bipolar scar percentages
patients, complete success was achieved in 50%,
among the 2 groups. The box represents the interquartile range;
partial success in 38%, and failure in 12%.
the vertical lines, the maximum and minimum values; and the horizontal line, the median (18.4 in the death/transplantation/ LVAD group vs. 10.9 in the group not experiencing an endpoint, p ¼ 0.001).
COX
PROPORTIONAL
DERIVATION
OF
RISK
HAZARD
MODELING
SCORE. Using
AND
univariate
testing, older age, lower LVEF, higher NYHA heart failure class, higher creatinine, VT storm, greater QRS DURATION AND MORPHOLOGY. The presenting
rhythm on ECG immediately preceding ablation was biventricular paced in 42 patients, right ventricular paced in 7 patients, left bundle branch block in 7 patients, right bundle branch block in 7 patients, and normal or intraventricular conduction delay in 37 patients (Figure 1). In 25 patients, ECGs of native conduction were not available on the day of ablation but were available on previous ECGs, performed a median of 29 days earlier (interquartile range: 3 to 509 days). Of the 49 patients presenting in a paced rhythm, 18 patients had underlying left bundle branch block, 10 patients had right bundle branch block, and 13 patients had normal or intraventricular conduction delay. Eight patients had no native rhythm underlying pacing and were not included in the QRS duration survival analysis. Left bundle branch block was more common among patients who experienced the primary endpoint than among those who did not (41.7% vs. 17.9%, p ¼ 0.01) (Table 1, Figure 1). Native QRS duration was greater among those who experienced death, transplantation, or LVAD. The difference was significant when combining all native QRS morphologies (151.7 38.2 ms vs. 128.9 31.5 ms,
number of spontaneous or induced VTs, diuretic use, amiodarone use, larger endocardial unipolar low voltage area, larger endocardial or epicardial bipolar scar percentage (whichever was greater), acute procedural success and longer native QRS duration were all associated with shorter time to death, heart transplantation, or LVAD (Table 2). In multivariate analysis, lower LVEF, VT storm, larger endocardial or epicardial bipolar scar percentage (whichever was greater), and longer native QRS duration remained independently associated with shorter time to death, heart transplantation, or LVAD. Accordingly, these 4 variables were weighted in proportion to their b regression coefficients and combined to create a risk score. To maximize ease of use and thereby clinical utility, b regression coefficients were converted to points by dividing all coefficients by the value of the lowest coefficient (0.012) and then rounding to the nearest integer, as follows. Risk score ¼ ðVT storm 83Þ þ ðgreater of endocardial or epicardial bipolar scar percentage 4Þ þ ðQRS durationÞ ðLVEF 3Þ
p ¼ 0.002) (Figure 2A) and when limiting the comparison to patients with normal or intraventricular
Risk scores were then calculated for each patient
conduction delay morphologies (123.8 27.1 ms vs.
and cutoffs selected to divide the population into
109.1 16.1 ms, p ¼ 0.02) (Figure 2B). There was a
equally sized thirds. High risk was defined as risk
directionally consistent, nonsignificant trend toward
score >180 points, intermediate risk 100 to 180, and
greater QRS duration among patients experiencing
low risk <100. For example, a patient who presented
403
404
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Wider QRS/Larger Scar Predict Worse NICM Survival
T A B L E 2 Factors Predictive of Time to Death, Heart Transplantation, or LVAD
Univariate Hazard Ratio
Age (per 1-yr increase)
1.03
Left ventricular ejection fraction (per 1% increase) New York Heart Association heart failure class
Multivariate
Scoring System
95% CI
p Value
Hazard Ratio
95% CI
p Value
1.00–1.06
0.03
1.03
0.99–1.07
0.10
0.96
0.93–0.98
0.001
0.96
0.92–0.99
0.02
1.55
1.05–2.23
0.03
1.62
0.98–2.67
0.06
Creatinine (per 1 mg/dl increase)
3.09
1.93–4.94
<0.001
1.35
0.67–2.71
0.40
Ventricular tachycardia storm
2.06
1.08–3.92
0.03
2.82
1.12–6.75
0.02
Number of VTs occurring spontaneously or induced (per 1 additional VT)
1.35
1.14–1.60
<0.001
1.05
0.82–1.34
0.70
Diuretic use
2.57
1.08–6.13
0.03
2.02
0.72–5.62
0.50
Amiodarone use
2.49
1.18–5.24
0.02
2.03
0.54–3.60
0.50
Endocardial unipolar low voltage percentage (per 1% increase)
1.02
1.01–1.03
0.005
0.99
0.97–1.01
0.30
Greater of endocardial or epicardial bipolar scar (per 1% increase)
1.04
1.01–1.07
0.004
1.07
1.03–1.12
0.003
Acute procedural success
0.61
0.37–1.01
0.05
0.54
0.28–1.04
0.06
Native QRS duration (per 1 ms increase)
1.02
1.01–1.03
0.001
1.01
1.00–1.03
0.05
b Regression Coefficient
Points
0.031
3
0.977
83
0.05
4
0.012
1
Risk score ¼ (VT storm 83) þ (greater of endocardial or epicardial bipolar scar percentage 4) þ (QRS duration) (LVEF 3). Risk score >180 ¼ high risk. Risk score 100 to 180 ¼ intermediate risk. Risk score <100 ¼ low risk. CI ¼ confidence interval; VT ¼ ventricular tachycardia.
with VT storm, bipolar scar percentage 25, QRS
ventricular ejection fraction 20 would have a risk
duration 170 ms, and LVEF 20 would have a risk
score ¼ 0 þ 20 þ 120 – 60 ¼ 80 (low risk).
score ¼ 83 þ 100 þ 170 60 ¼ 293 (high risk). A pa-
Kaplan-Meier
curves
were
then
constructed
tient who presented without VT storm, with bipolar
comparing 2-year transplantation/LVAD-free survival
scar percentage 5, QRS duration 120 ms, and left
among the high-, intermediate-, and low-risk groups. Survival was worse in the high-risk group compared
F I G U R E 4 Heart Transplantation- and LVAD-Free Survival in the Derivation Cohort by
Risk Group
with the intermediate- and low-risk groups (<40% vs. 70% and >90% respectively, p < 0.001 for trend across groups) (Figure 4). Rates of 1-year transplantation/LVAD-free survival were 50%, 75%, and >90%, respectively. The area under the risk score receiver operating characteristic curve was 0.79 for the derivation cohort. VALIDATION OF RISK SCORE. Of the 50 patients in
the validation cohort, 20 patients were classified as high risk, 15 patients as intermediate risk, and 15 patients as low risk. Baseline characteristics of the validation cohort, stratified by risk group, are provided in Table 3. During 3.0 years mean follow-up (range 9 days to 10.3 years), 17 (85%) patients in the high-risk group died or underwent transplantation/LVAD, compared with 7 (47%) patients in the intermediate-risk group and 2 (13%) patients in the low-risk group (Table 3). One patient in the high-risk group underwent LVAD implantation followed by transplantation and subsequently died 6 months later. Of the 49 deaths in the Kaplan-Meier curves are shown for the high-risk, intermediate-risk, and low-risk groups (<40% vs. 70% and >90%, respectively, p < 0.001 for trend across groups). The risk score ¼ (VT storm 83) þ (greater of endocardial or epicardial bipolar scar percentage 4) þ
derivation and validation cohorts, the cause of death could be identified in 14 patients. Of these 14, causes of
(QRS duration) (LVEF 3). A risk score >180 ¼ high risk, 100 to 180 ¼ intermediate risk
death were infection in 3 patients, cardiogenic shock in
and <100 ¼ low risk. LVAD ¼ left ventricular assist device.
2 patients, stroke in 2 patients, complication of an unrelated procedure in 2 patients, pulseless electrical
Frankel et al.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 1, NO. 5, 2015 OCTOBER 2015:398–407
activity in 2 patients, complication of VT ablation in 1 patient, refractory VT in 1 patient, and trauma
T A B L E 3 Baseline Characteristics and Clinical Outcomes of Validation Cohort
High Risk (n ¼ 20)
in 1 patient. In Kaplan-Meier analysis, transplantation and LVAD-free survival was worse in the high-risk group
405
Wider QRS/Larger Scar Predict Worse NICM Survival
Intermediate Risk (n ¼15)
Low Risk
Baseline characteristics 90.0
40.0
13.3
Greater of endocardial or epicardial bipolar scar percentage
16.9 22.1
10.2 7.1
6.3 7.3
trend across groups) (Figure 5). The area under the
QRS duration, ms
141.7 35.6
150.1 32.9
116.9 34.0
risk score receiver operating characteristic curve was
Left ventricular ejection fraction, %
30.6 15.0
28.8 10.8
46.3 10.8
285.5 92.7
136.5 23.2
13.8 58.6 0.0
compared with the intermediate- and low-risk groups (<10% vs. 50% and >80% respectively, p < 0.001 for
0.82 for the validation cohort. A cutoff score of 100 was highly sensitive for development of the primary
Ventricular tachycardia storm, %
EP risk score Clinical outcomes Left ventricular assist device, %
5.0
0.0
endpoint by 3 years (sensitivity 93.5%, specificity
Heart transplantation, %
35.0
6.7
0.0
54.7%), whereas a cutoff of 180 was more specific
Death, %
55.0
40.0
13.3
(sensitivity 64.7%, specificity 85.8%). Values are % or mean SD.
DISCUSSION In particular, unipolar voltage mapping may have In a moderate-sized group of contemporary patients
even greater sensitivity for identifying subtle areas
with NICM presenting for VT ablation, we identified
of abnormality. For example, larger areas of unipolar
wider native QRS duration, greater endocardial or
voltage abnormality were recently shown to predict
epicardial bipolar scar percentage, VT storm, and
irreversibility of NICM in patients without scar
LVEF as independent predictors of shorter time to
detected by MRI or bipolar voltage mapping (16).
death, transplantation, or LVAD. By combining these
In contrast to a recent multicenter report (17), acute
variables into an “electrophysiological risk score,” we
procedural success was not significantly associated
were able to discriminate among patients at high-,
with the primary endpoint in our multivariate model
intermediate-, and low-risk for major adverse events
(p ¼ 0.06). It is likely that with a larger sample size, the
over medium-term follow-up. We subsequently vali-
association would have been statistically significant.
dated the risk score in a separate group of patients
Through the incorporation of electrophysiological
with longer-term follow-up, and it again predicted
risk factors, we aimed to improve risk stratification of
risk with a high degree of accuracy.
patients with NICM beyond LVEF. Should our risk
Whereas left bundle branch block has long been established as a risk factor for adverse heart failure outcomes (13), we further showed that QRS width, within each category of QRS morphology, further pre-
F I G U R E 5 Heart Transplantation- and LVAD-Free Survival in the Validation Cohort by
Risk Group
dicts risk. For example, among those with normal QRS morphology or intraventricular conduction delay, greater QRS width predicted shorter time to death, transplantation, or LVAD. This observation was directionally consistent, although not statistically significant, across all QRS morphology categories. Within a given QRS morphology category, increasing QRS width is likely a manifestation of slower cell-to-cell conduction, potentially a result of increased fibrosis (14). Scar size as assessed by MRI has been shown to predict death and need for heart transplantation among patients with ischemic cardiomyopathy, independently of LVEF (15). More recently, this finding was replicated among patients with NICM (3). Thus, it is not surprising that larger scars, as identified by bipolar voltage mapping, would predict worse prognosis among patients with NICM presenting with VT.
Kaplan-Meier curves are shown for the high-risk, intermediate-risk, and low-risk groups
In fact, careful voltage mapping with good contact
(<10% vs. 50% and >80%, respectively, p < 0.001 for trend across groups). LVAD ¼ left
and sampling density may be a more sensitive tech-
ventricular assist device.
nique than MRI for detection of myocardial scarring.
406
Frankel et al.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 1, NO. 5, 2015 OCTOBER 2015:398–407
Wider QRS/Larger Scar Predict Worse NICM Survival
score be validated in other populations, measurement
predictors of shorter time to death, transplantation,
of QRS duration and voltage mapping could be used as
or LVAD in patients with NICM and VT. By combining
part of a baseline electrophysiological evaluation,
these variables into an electrophysiological risk score,
which, when combined with LVEF, could provide
patients can be classified as high-, intermediate-, or
valuable prognostic information. This information
low-risk for major adverse outcomes.
could then be used to counsel patients and guide the intensity of their heart failure follow-up and in-
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
terventions. Physicians caring for high-risk patients
David S. Frankel, Cardiovascular Division, Electro-
could intensify neurohormonal modulators as aggres-
physiology Section, Hospital of the University of
sively as possible and have a lower threshold for
Pennsylvania, 9 Founders Pavilion, 3400 Spruce
referral to advanced heart failure programs special-
Street, Philadelphia, Pennsylvania 19104. E-mail:
izing in LVAD, transplantation, and other cutting-
[email protected].
edge/experimental treatments. STUDY LIMITATIONS. Although our electrophysio-
logical risk score performed well in this single-center study, it should be validated in other centers. Further, to determine the range of its applicability, the
PERSPECTIVES COMPETENCY IN MEDICAL KNOWLEDGE: In
risk score would also need to be tested in different
addition to LVEF, we identified wider native QRS
patient populations, such as patients with NICM
duration, increased scar percentage detected by
without VT and patients with ischemic cardiomyopa-
electroanatomic mapping, and VT storm as indepen-
thy. Our risk score cannot be calculated in those
dent predictors of shorter time to death, transplan-
without intrinsic atrioventricular conduction, as
tation, or LVAD in patients with nonischemic
native QRS duration is required. Not all patients
cardiomyopathy. We combined these factors to create
underwent epicardial voltage mapping. However, all
an electrophysiological risk score that accurately
patients did undergo endocardial unipolar voltage
divided patients into high-, intermediate-, and low-
mapping, which has been shown to predict the extent
risk categories.
and distribution of midmyocardial and epicardial scar (8). Lastly, the threshold to implant an LVAD or perform a heart transplantation may vary from institution to institution.
TRANSLATIONAL OUTLOOK: Should our risk score be validated in different populations, measurement of QRS duration and voltage mapping could be performed as a baseline electrophysiological evaluation, which, when combined with LVEF, could provide
CONCLUSIONS
more accurate prognostic information. This could then
We identified wider native QRS duration, greater endocardial or epicardial bipolar scar percentage, and
be used to guide the intensity of heart failure followup and interventions.
VT storm, in addition to LVEF, as independent
REFERENCES 1. Tokuda M, Tedrow UB, Kojodjojo P, et al. Catheter ablation of ventricular tachycardia in nonischemic heart disease. Circ Arrhythm Electrophysiol 2012;5:992–1000. 2. Sauer WH, Zado E, Gerstenfeld EP, Marchlinski FE, Callans DJ. Incidence and predictors of mortality following ablation of ventricular tachycardia in patients with an implantable cardioverter-defibrillator. Heart Rhythm 2010;7:9–14. 3. Gulati A, Jabbour A, Ismail TF, et al. Association of fibrosis with mortality and sudden cardiac death in patients with nonischemic dilated cardiomyopathy. JAMA 2013;309:896–908. 4. Iuliano S, Fisher SG, Karasik PE, Fletcher RD, Singh SN. QRS duration and mortality in patients with congestive heart failure. Am Heart J 2002; 143:1085–91.
5. Shamim W, Yousufuddin M, Cicoria M, Gibson DG, Coats AJ, Henein MY. Incremental changes in QRS duration in serial ECGs over time identify high risk elderly patients with heart failure. Heart 2002;88:47–51. 6. Surawicz B, Childers R, Deal BJ, et al. AHA/ ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part III: intraventricular conduction disturbances: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society. Endorsed by the International Society for Computerized Electrocardiology. J Am Coll Cardiol 2009;53:976–81. 7. Cassidy DM, Vassallo JA, Miller JM, et al. Endocardial catheter mapping in patients in sinus
rhythm: relationship to underlying heart disease and ventricular arrhythmias. Circulation 1986;73: 645–52. 8. Hutchinson MD, Gerstenfeld EP, Desjardins B, et al. Endocardial unipolar voltage mapping to detect epicardial ventricular tachycardia substrate in patients with nonischemic left ventricular cardiomyopathy. Circ Arrhythm Electrophysiol 2011;4: 49–55. 9. Bazan V, Gerstenfeld EP, Garcia FC, et al. Sitespecific twelve-lead ECG features to identify an epicardial origin for left ventricular tachycardia in the absence of myocardial infarction. Heart Rhythm 2007;4:1403–10. 10. Marchlinski FE, Callans DJ, Gottlieb CD, Zado E. Linear ablation lesions for control of unmappable ventricular tachycardia in patients
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with ischemic and nonischemic cardiomyopathy. Circulation 2000;101:1288–96. 11. Cano O, Hutchinson M, Lin D, et al. Electroanatomic substrate and ablation outcome for suspected epicardial ventricular tachycardia in left ventricular nonischemic cardiomyopathy. J Am Coll Cardiol 2009;54:799–808.
Wider QRS/Larger Scar Predict Worse NICM Survival
and total mortality in the multicenter unsustained tachycardia trial. Circulation 2004;110:766–9. 14. de Bakker JM, van Rijen HM. Continuous and discontinuous propagation in heart muscle. J Cardiovasc Electrophysiol 2006;17:567–73.
fat can mimic scar. J Cardiovasc Electrophysiol 2003;14:1128.
15. Kwon DH, Halley CM, Carrigan TP, et al. Extent of left ventricular scar predicts outcomes in ischemic cardiomyopathy patients with significantly reduced systolic function: a delayed hyperenhancement cardiac magnetic resonance study. J Am Coll Cardiol Img 2009;2:34–44.
13. Zimetbaum PJ, Buxton AE, Batsford W, et al. Electrocardiographic predictors of arrhythmic death
16. Campos B, Jauregui ME, Park KM, et al. New unipolar electrogram criteria to identify
12. Dixit S, Narula N, Callans DJ, Marchlinski FE. Electroanatomic mapping of human heart: epicardial
irreversibility of nonischemic left ventricular cardiomyopathy. J Am Coll Cardiol 2012;60: 2194–204. 17. Yokokawa M, Kim HM, Baser K, et al. Predictive value of programmed ventricular stimulation after catheter ablation of post-infarction ventricular tachycardia. J Am Coll Cardiol 2015; 65:1954–9.
KEY WORDS bipolar scar, electroanatomic mapping, heart failure, nonischemic cardiomyopathy, QRS duration
407
VOL. 1, NO. 5, 2015
ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 2405-500X/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jacep.2015.07.005
Electrophysiological Predictors of Transplantation and Left Ventricular Assist Device-Free Survival in Patients With Nonischemic Cardiomyopathy Undergoing Ventricular Tachycardia Ablation David S. Frankel, MD, Jackson J. Liang, DO, Gregory Supple, MD, Sanjay Dixit, MD, Mathew D. Hutchinson, MD, Melissa A. Elafros, PHD, David J. Callans, MD, Francis E. Marchlinski, MD
ABSTRACT OBJECTIVES This study sought to identify predictors of transplantation/left ventricular assist device (LVAD)-free survival among patients with left ventricular nonischemic cardiomyopathy (NICM) and ventricular tachycardia (VT). BACKGROUND Outcomes vary widely among these patients. METHODS The derivation cohort consisted of patients with NICM undergoing VT ablation from 2007 to 2011. Scar percentage was defined as the area of low voltage divided by total surface area. Cox proportional hazard modeling was performed to identify predictors of shorter time to the primary endpoint of death, transplantation, or LVAD. A risk score was created using b regression coefficients. The risk score was then validated in a separate cohort of patients undergoing ablation from 2004 to 2007. RESULTS Of 100 patients with NICM undergoing VT ablation, 41 experienced an endpoint during 1.2 years mean follow-up. In multivariate modeling, VT storm, wider native QRS duration, greater endocardial/epicardial bipolar scar percentage, and lower left ventricular ejection fraction (LVEF) identified worse transplantation/LVAD-free survival. The risk score ¼ (VT storm 83) þ (greater of endocardial/epicardial bipolar scar percentage 4) þ (QRS duration) (LVEF 3). A score >180 identified patients at high risk for the endpoint, whereas a score <100 identified low risk. Among the 50-patient validation cohort, the high-risk group again had worse transplantation/LVAD-free survival during a mean 3.0 years of follow-up (<10% vs. 50% for intermediate and >80% for low, p < 0.001). CONCLUSIONS Wider native QRS duration, greater bipolar scar percentage, VT storm, and lower LVEF are potent predictors of time to death, transplantation, or LVAD. By combining these variables into an “electrophysiological risk score,” patient risk can be refined. (J Am Coll Cardiol EP 2015;1:398–407) © 2015 by the American College of Cardiology Foundation.
T Listen to this manuscript’s audio summary by JACC:
he incidence of death, heart transplantation,
prognostic information and potentially guide more
or left ventricular assist device (LVAD) im-
intensive heart failure therapies.
plantation among patients with nonischemic
Greater extent of myocardial delayed enhancement
cardiomyopathy (NICM) presenting with ventricular
on cardiac magnetic resonance imaging (MRI) was
tachycardia (VT) is substantial (1,2). The ability to
recently shown to predict worse outcomes in patients
better risk stratify these patients beyond left ventric-
with NICM (3); however, this finding has yet to
ular ejection fraction (LVEF) could provide valuable
be replicated with other scar assessment modalities.
Clinical Electrophysiology Editor-in-Chief Dr. David J. Wilber. From the Cardiovascular Division, Electrophysiology Section, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania. Supported in part by the F. Harlan Batrus Research Fund and the Susan and Murray Bloom Fund. Dr. Marchlinski has served on scientific advisory boards and received research support from St. Jude Medical and Biosense Webster. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received April 13, 2015; revised manuscript received July 14, 2015, accepted July 16, 2015.
Frankel et al.
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399
Wider QRS/Larger Scar Predict Worse NICM Survival
Similarly, wider QRS duration has been inconsistently
present, QRS duration comparisons were
ABBREVIATIONS
related to mortality in patients with NICM (4,5). We
further stratified by QRS morphology category
AND ACRONYMS
hypothesized that larger areas of scar defined by low
(left bundle branch block, right bundle branch
voltage during electroanatomic mapping and wider
block, biventricular paced, right ventricular
QRS durations would predict worse transplantation-
paced). Left bundle branch block, right bundle
and LVAD-free survival among patients with NICM
branch block, and intraventricular conduction
and VT. We further sought to develop and then vali-
delay were defined according to standard
date an electrophysiological risk score to aid in risk
ECG criteria established by the American
stratifying patients with NICM and VT.
Heart Association, the American College of
SEE PAGE 408
METHODS STUDY POPULATION. The risk score was derived
from consecutive patients with left ventricular NICM and sustained VT who had been referred to the Hospital of the University of Pennsylvania for ablation between July 2007 and April 2011. Patients with idiopathic VT, right ventricular cardiomyopathy, or ischemic cardiomyopathy, as defined by history of myocardial infarction or obstructive coronary artery disease on angiography, were excluded. Patients undergoing multiple ablation procedures during this period were included once, with analysis of the voltage maps from the first procedure only. However, if epicardial mapping was not performed during the first procedure but was performed during a subsequent procedure, the subsequent epicardial map was analyzed. The risk score was validated in a separate cohort of consecutive patients with identical inclusion and exclusion criteria who had been referred to our institution for ablation between March 2004 and June 2007. VT storm was defined as 3 or more separate episodes of VT within 24 h. All patients provided written informed consent for catheter ablation and for their anonymized medical information to be included in research studies. MEASUREMENT OF QRS DURATION AND CLASSIFICATION
ECG = electrocardiogram LVAD = left ventricular assist device
LVEF = left ventricular ejection fraction
MRI = magnetic resonance imaging
Cardiology, and the Heart Rhythm Society (6).
NICM = nonischemic
ECGs were analyzed blinded to patient
cardiomyopathy
outcome.
VT = ventricular tachycardia
ELECTROANATOMIC MAPPING AND VT ABLATION. Electro-
anatomic mapping (CARTO, Biosense Webster, Diamond Bar, California) was performed during sinus or paced rhythm to define areas of low voltage and abnormal electrograms, consistent with scar (7), using a 3.5-mm open irrigation tip catheter (Navistar Thermocool, Biosense Webster) maintaining a fill threshold of 15 mm to ensure adequate sampling of the entire represented surface area. Bipolar electrograms were recorded between the distal and ring electrodes of the mapping catheter and filtered at 30 to 400 Hz. Endocardial unipolar electrograms were recorded between the distal electrode of the mapping catheter and Wilson’s central terminal and filtered at 1 to 240 Hz (8). All patients underwent endocardial mapping; epicardial mapping was performed when an ECG of spontaneous or induced VT suggested an epicardial exit (9) and/or endocardial ablation failed to eliminate targeted VT. Voltage maps were analyzed off-line using the CARTO area measurement software, with endocardial bipolar low voltage defined as <1.5 mV, endocardial unipolar as <8.3 mV, and epicardial bipolar as <1.0 mV (10,11). To avoid misclassification of epicardial fat or coronary arteries as scar, areas of epicardial bipolar voltage <1.0 mV were only considered scar if wide,
OF QRS MORPHOLOGY. The presenting QRS duration,
split, or late electrograms were also present (12). Scar
whether paced or conducted, was measured using
percentage was defined as the area of low voltage
digital calipers on the 12-lead electrocardiogram (ECG)
divided by the entire surface area of the mapped
immediately preceding VT ablation. For patients pre-
chamber, multiplied by 100. Because some patients
senting in VT, QRS duration was measured on a prior
did not undergo epicardial mapping and to account
ECG or the recordings from the VT ablation (CardioLab,
for the fact that some patients have greater endocar-
GE Medical Systems, Waukesha, Wisconsin) not during
dial bipolar scar percentage whereas others have
VT. For patients presenting in paced rhythm, prior
greater epicardial bipolar scar percentage, a single
ECGs/ablation recordings were similarly searched to
combined
identify and measure native QRS complexes. QRS du-
epicardial bipolar scar percentage,” was created to
rations were compared between those experiencing
most accurately reflect total scar burden. Voltage
death, transplantation, or LVAD and those not expe-
maps were analyzed blinded to patient outcome.
riencing the primary endpoint. Because QRS durations
After
variable,
“greater
of
endocardial
or
electroanatomic mapping, VT induction
would be expected to vary widely on the basis of
was performed. Programmed stimulation was deli-
whether bundle branch block or paced rhythm were
vered from the right and left ventricles, with up to
400
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Wider QRS/Larger Scar Predict Worse NICM Survival
3 extrastimuli delivered to refractoriness. When a
30 ms of stored electrograms from spontaneous VT
12-lead ECG of spontaneous VT was available, clinical
episodes. Every spontaneously occurring VT was
VT was defined by match in all 12 leads. When a
considered clinical; thus, a single patient could have
12-lead ECG of spontaneous VT was not available,
multiple clinical VTs. Special attention was paid to
clinical VT was defined by match in near-field and
elimination of clinical VT. Additionally, all mappable
far-field implantable cardioverter-defibrillator elec-
VT and VT with cycle length >250 ms were also
trogram morphology, as well as cycle length within
considered relevant and routinely targeted for ablation. When hemodynamically tolerated, entrainment mapping was used to define critical components of
T A B L E 1 Baseline Characteristics of Derivation Cohort According to Whether Death,
the VT circuit. If VT was not mappable, substrate modification was performed with linear and/or cluster
Transplant, or LVAD Occurred During Follow-Up
lesions targeting exit sites identified by pace-mapping
Death, Transplantation, or LVAD
as well as late potentials. Ablation settings included
Yes (n ¼ 41)
No (n ¼ 59)
p Value
Male, %
90.2
83.1
0.40
grammed stimulation was repeated in patients who
Age, yrs
65.8 11.9
59.2 12.7
0.01
8.9 7.2
7.2 6.3
were medically stable, with up to 3 ventricular extra-
0.20
23.4 12.0
35.4 16.0
<0.001
12 to 15 ohm impedance drop. After ablation, pro-
Baseline characteristics
Years since diagnosis of nonischemic cardiomyopathy Left ventricular ejection fraction, %
power up to 50 W, with temperature limit 42 and goal
stimuli delivered from 2 sites at 2 pacing cycle lengths. Acute procedural success was defined as elimination of all VT. Partial success was defined as elimination of all
NYHA heart failure class
0.02
Class I
29.3
57.6
Class II
48.8
33.9
Class III
17.1
8.5
Class IV
4.9
0.0
clinical VT. Failure was defined as persistent inducibility of clinical VT. CLINICAL FOLLOW-UP. The primary endpoint was
defined as death, heart transplantation, or LVAD
1.6 0.6
1.2 0.3
<0.001
Diabetes, %
26.8
16.9
0.30
Hypertension, %
63.4
55.9
0.90
4.9
5.1
0.90
tervals. Defibrillators were interrogated at each visit
Creatinine, mg/dl
Chronic obstructive pulmonary disease, %
implantation. Patients were routinely evaluated at 6 weeks after ablation and then at 3- to 6-month in-
Thyroid disease, %
34.1
27.1
0.50
to assess for VT recurrence. For patients not followed
Implantable cardioverter defibrillator present, %
97.6
93.2
0.70
at our institution, referring cardiologists were con-
Cardiac resynchronization therapy device present, %
65.9
25.4
<0.001
Ventricular tachycardia storm, %
63.4
42.1
0.04
4.0 1.6
3.0 1.7
0.006
9.8
8.5
1.00
Beta-blocker, %
95.1
83.1
0.10
categorical variables are expressed as percentages.
ACE inhibitor or angiotensin receptor blocker, %
75.6
78.0
0.80
The independent samples Student t test and Pear-
Diuretic, %
85.4
59.3
0.01
son chi-square test were used to compare normally
Amiodarone, %
78.0
52.5
0.01
distributed continuous and dichotomous variables,
Presenting QRS duration (including paced), ms
173.4 37.1
137.6 36.1
<0.001
Native QRS duration, ms
151.7 38.2
128.9 31.5
0.002
Left bundle branch block, %
41.7
17.9
0.01
Right bundle branch block, %
16.7
19.6
0.80
were followed until death, transplantation, LVAD, or
Endocardial bipolar scar, %
16.7 12.8
8.7 8.6
0.001
predictors of time to the primary endpoint using Cox
Endocardial unipolar low voltage, %
54.4 30.3
28.8 21.4
<0.001
proportional hazard modeling. Variables subjected
56.1
59.3
0.90
to univariate screening included age, LVEF, New
18.4 12.3
10.9 8.7
0.001
York Heart Association (NYHA) heart failure class,
Number of ventricular tachycardias occurring spontaneously or induced Atrial fibrillation present on admission, %
social security death index was also queried. STATISTICAL ANALYSIS, DERIVATION OF RISK SCORE, AND VALIDATION OF RISK SCORE. Continuous variables
respectively. The Fisher exact test was used to compare
QRS complex
dichotomous variables with expected cell values <5. The Mann-Whitney U test was used to compare nonnormally distributed continuous variables. Patients the most recent clinical evaluation. We identified
Voltage mapping
Bipolar scar percentage, greater of endocardial or epicardial
patients or family members every 6 to 12 months. The
are expressed as means with standard deviations, and
Baseline medications
Epicardial mapping, %
tacted and telephone interviews performed with
creatinine, VT storm, number of spontaneous and Values are % or mean SD.
induced VTs, acute procedural success, diuretic use,
ACE ¼ angiotensin-converting enzyme; LVAD ¼ left ventricular assist device; NYHA ¼ New York Heart Association.
amiodarone use, endocardial unipolar low voltage percentage, greater of endocardial or epicardial
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Wider QRS/Larger Scar Predict Worse NICM Survival
bipolar scar percentage, and native QRS duration. The
low-risk groups using the cutoffs established in the
assumption of proportional hazards was tested and
derivation cohort. Again, Kaplan-Meier curves were
confirmed. Patients without natively conducted QRS
constructed and transplantation/LVAD-free survival
complexes were excluded from QRS duration survival
compared between the risk groups using a log-rank
analysis. Variables showing marginal associations with
test. A receiver operating characteristic curve was
time to death, transplantation, or LVAD on univariate
plotted for the risk score to assess sensitivity and
testing (p < 0.10) were assessed in a multivariate
specificity for 3-year outcomes. Analyses were per-
model.
formed using SPSS (version 20.0, SPSS Inc., Chicago,
Variables retaining significant, independent asso-
Illinois) and R (Foundation for Statistical Computing,
ciations with time to death, transplantation, or LVAD
Vienna, Austria). We considered p values #0.05 to
on multivariate testing were included in the risk score.
indicate statistical significance.
These variables were assigned weighted points in proportion to their b regression coefficient values,
RESULTS
rounded to the nearest integer. By adding these points, an overall risk score was calculated. Cutoffs were
BASELINE CHARACTERISTICS AND OUTCOMES OF
established to divide the population into equally sized
DERIVATION COHORT. Of 100 patients with NICM
high-, intermediate-, and low-risk groups. We then
undergoing VT ablation, 49 recurred over a mean
constructed Kaplan-Meier curves to illustrate trans-
follow-up of 1.2 years (range 3 days to 4.8 years).
plantation and LVAD-free survival and compared
Among these 49, recurrent VT was treated exclusively
the high-, intermediate-, and low-risk groups using a
with antitachycardia pacing in 44% and with at least 1
log-rank test.
implantable cardioverter-defibrillator shock in 56%.
Next, we validated the risk score in a separate pop-
Forty-one patients experienced the primary study
ulation with NICM and VT. Risk scores were calculated
endpoint (3 LVADs, 12 transplantations, and 29
and subjects assigned to high-, intermediate-, and
deaths). Two patients underwent LVAD implantation
F I G U R E 1 QRS Morphology Categories
Presenting and underlying QRS morphologies are illustrated. The number of patients experiencing and not experiencing the primary endpoint (death, transplantation, or LVAD) is provided within each QRS morphology category. Patients who experienced an endpoint were more likely to present with biventricular pacing (p < 0.001) and to have underlying left bundle branch block (p ¼ 0.01). BiV ¼ biventricular; IVCD ¼ intraventricular conduction delay; LBBB ¼ left bundle branch block; LVAD ¼ left ventricular assist device; RBBB ¼ right bundle branch block; RV ¼ right ventricular.
401
402
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Wider QRS/Larger Scar Predict Worse NICM Survival
followed by transplantation. One patient underwent
endpoint were older at the time of presentation, with
LVAD implantation and later died. The majority of
lower LVEF, higher NYHA heart failure class, higher
LVAD implantations and transplantations were per-
creatinine, more likely to present in VT storm, with a
formed for end-stage heart failure; 3 were performed
greater number of VTs occurring spontaneously or
for refractory ventricular arrhythmias. Compared
induced, more likely to have a cardiac resynchroni-
with those who survived the study period without
zation therapy device, and more likely to be taking a
transplantation or LVAD, those who experienced an
diuretic or amiodarone (Table 1).
F I G U R E 2 Distribution of QRS Durations Based on Whether Death, Transplantation, or LVAD Occurred, Stratified by QRS Morphology
Box plots illustrate the distribution of QRS durations among the 2 groups. The box represents the interquartile range; the vertical lines, the maximum and minimum values; and the horizontal line, the median. The number of patients in each category is provided next to that box. (A) Compares all native QRS durations. (B) Compares only normal and intraventricular conduction delay morphologies. (C) Compares only left bundle branch block morphologies. (D) Compares only right bundle branch block morphologies. (E) Compares only biventricular paced morphologies. (F) Compares only right ventricular paced morphologies. Abbreviations as in Figure 1.
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F I G U R E 3 Distribution of Greater of Endocardial or
Epicardial Bipolar Scar Percentage Based on Whether Death, Transplant, or LVAD Occurred
Wider QRS/Larger Scar Predict Worse NICM Survival
the endpoint in each additional QRS morphology category (left bundle branch block, right bundle branch block, biventricular paced, and right ventricular paced, p ¼ 0.2, 0.7, 0.2, and 0.2, respectively) (Figures 2C to 2F). VOLTAGE MAPPING AND ABLATION. A mean of 357
points were sampled per endocardial voltage map and 506 points per epicardial voltage map. Patients who went on to experience the endpoint had a greater percentage of endocardial bipolar scar (16.7 12.8 vs. 8.7 8.6, p ¼ 0.001) (Table 1), endocardial unipolar low voltage area (54.4 30.3 vs. 28.8 21.4, p < 0.001), and greater of endocardial or epicardial bipolar scar (18.4 12.3 vs. 10.9 8.7, p ¼ 0.001) (Figure 3). Programmed stimulation was performed at the end of ablation in 80% of patients. Among these Box plots illustrate the distribution of bipolar scar percentages
patients, complete success was achieved in 50%,
among the 2 groups. The box represents the interquartile range;
partial success in 38%, and failure in 12%.
the vertical lines, the maximum and minimum values; and the horizontal line, the median (18.4 in the death/transplantation/ LVAD group vs. 10.9 in the group not experiencing an endpoint, p ¼ 0.001).
COX
PROPORTIONAL
DERIVATION
OF
RISK
HAZARD
MODELING
SCORE. Using
AND
univariate
testing, older age, lower LVEF, higher NYHA heart failure class, higher creatinine, VT storm, greater QRS DURATION AND MORPHOLOGY. The presenting
rhythm on ECG immediately preceding ablation was biventricular paced in 42 patients, right ventricular paced in 7 patients, left bundle branch block in 7 patients, right bundle branch block in 7 patients, and normal or intraventricular conduction delay in 37 patients (Figure 1). In 25 patients, ECGs of native conduction were not available on the day of ablation but were available on previous ECGs, performed a median of 29 days earlier (interquartile range: 3 to 509 days). Of the 49 patients presenting in a paced rhythm, 18 patients had underlying left bundle branch block, 10 patients had right bundle branch block, and 13 patients had normal or intraventricular conduction delay. Eight patients had no native rhythm underlying pacing and were not included in the QRS duration survival analysis. Left bundle branch block was more common among patients who experienced the primary endpoint than among those who did not (41.7% vs. 17.9%, p ¼ 0.01) (Table 1, Figure 1). Native QRS duration was greater among those who experienced death, transplantation, or LVAD. The difference was significant when combining all native QRS morphologies (151.7 38.2 ms vs. 128.9 31.5 ms,
number of spontaneous or induced VTs, diuretic use, amiodarone use, larger endocardial unipolar low voltage area, larger endocardial or epicardial bipolar scar percentage (whichever was greater), acute procedural success and longer native QRS duration were all associated with shorter time to death, heart transplantation, or LVAD (Table 2). In multivariate analysis, lower LVEF, VT storm, larger endocardial or epicardial bipolar scar percentage (whichever was greater), and longer native QRS duration remained independently associated with shorter time to death, heart transplantation, or LVAD. Accordingly, these 4 variables were weighted in proportion to their b regression coefficients and combined to create a risk score. To maximize ease of use and thereby clinical utility, b regression coefficients were converted to points by dividing all coefficients by the value of the lowest coefficient (0.012) and then rounding to the nearest integer, as follows. Risk score ¼ ðVT storm 83Þ þ ðgreater of endocardial or epicardial bipolar scar percentage 4Þ þ ðQRS durationÞ ðLVEF 3Þ
p ¼ 0.002) (Figure 2A) and when limiting the comparison to patients with normal or intraventricular
Risk scores were then calculated for each patient
conduction delay morphologies (123.8 27.1 ms vs.
and cutoffs selected to divide the population into
109.1 16.1 ms, p ¼ 0.02) (Figure 2B). There was a
equally sized thirds. High risk was defined as risk
directionally consistent, nonsignificant trend toward
score >180 points, intermediate risk 100 to 180, and
greater QRS duration among patients experiencing
low risk <100. For example, a patient who presented
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Wider QRS/Larger Scar Predict Worse NICM Survival
T A B L E 2 Factors Predictive of Time to Death, Heart Transplantation, or LVAD
Univariate Hazard Ratio
Age (per 1-yr increase)
1.03
Left ventricular ejection fraction (per 1% increase) New York Heart Association heart failure class
Multivariate
Scoring System
95% CI
p Value
Hazard Ratio
95% CI
p Value
1.00–1.06
0.03
1.03
0.99–1.07
0.10
0.96
0.93–0.98
0.001
0.96
0.92–0.99
0.02
1.55
1.05–2.23
0.03
1.62
0.98–2.67
0.06
Creatinine (per 1 mg/dl increase)
3.09
1.93–4.94
<0.001
1.35
0.67–2.71
0.40
Ventricular tachycardia storm
2.06
1.08–3.92
0.03
2.82
1.12–6.75
0.02
Number of VTs occurring spontaneously or induced (per 1 additional VT)
1.35
1.14–1.60
<0.001
1.05
0.82–1.34
0.70
Diuretic use
2.57
1.08–6.13
0.03
2.02
0.72–5.62
0.50
Amiodarone use
2.49
1.18–5.24
0.02
2.03
0.54–3.60
0.50
Endocardial unipolar low voltage percentage (per 1% increase)
1.02
1.01–1.03
0.005
0.99
0.97–1.01
0.30
Greater of endocardial or epicardial bipolar scar (per 1% increase)
1.04
1.01–1.07
0.004
1.07
1.03–1.12
0.003
Acute procedural success
0.61
0.37–1.01
0.05
0.54
0.28–1.04
0.06
Native QRS duration (per 1 ms increase)
1.02
1.01–1.03
0.001
1.01
1.00–1.03
0.05
b Regression Coefficient
Points
0.031
3
0.977
83
0.05
4
0.012
1
Risk score ¼ (VT storm 83) þ (greater of endocardial or epicardial bipolar scar percentage 4) þ (QRS duration) (LVEF 3). Risk score >180 ¼ high risk. Risk score 100 to 180 ¼ intermediate risk. Risk score <100 ¼ low risk. CI ¼ confidence interval; VT ¼ ventricular tachycardia.
with VT storm, bipolar scar percentage 25, QRS
ventricular ejection fraction 20 would have a risk
duration 170 ms, and LVEF 20 would have a risk
score ¼ 0 þ 20 þ 120 – 60 ¼ 80 (low risk).
score ¼ 83 þ 100 þ 170 60 ¼ 293 (high risk). A pa-
Kaplan-Meier
curves
were
then
constructed
tient who presented without VT storm, with bipolar
comparing 2-year transplantation/LVAD-free survival
scar percentage 5, QRS duration 120 ms, and left
among the high-, intermediate-, and low-risk groups. Survival was worse in the high-risk group compared
F I G U R E 4 Heart Transplantation- and LVAD-Free Survival in the Derivation Cohort by
Risk Group
with the intermediate- and low-risk groups (<40% vs. 70% and >90% respectively, p < 0.001 for trend across groups) (Figure 4). Rates of 1-year transplantation/LVAD-free survival were 50%, 75%, and >90%, respectively. The area under the risk score receiver operating characteristic curve was 0.79 for the derivation cohort. VALIDATION OF RISK SCORE. Of the 50 patients in
the validation cohort, 20 patients were classified as high risk, 15 patients as intermediate risk, and 15 patients as low risk. Baseline characteristics of the validation cohort, stratified by risk group, are provided in Table 3. During 3.0 years mean follow-up (range 9 days to 10.3 years), 17 (85%) patients in the high-risk group died or underwent transplantation/LVAD, compared with 7 (47%) patients in the intermediate-risk group and 2 (13%) patients in the low-risk group (Table 3). One patient in the high-risk group underwent LVAD implantation followed by transplantation and subsequently died 6 months later. Of the 49 deaths in the Kaplan-Meier curves are shown for the high-risk, intermediate-risk, and low-risk groups (<40% vs. 70% and >90%, respectively, p < 0.001 for trend across groups). The risk score ¼ (VT storm 83) þ (greater of endocardial or epicardial bipolar scar percentage 4) þ
derivation and validation cohorts, the cause of death could be identified in 14 patients. Of these 14, causes of
(QRS duration) (LVEF 3). A risk score >180 ¼ high risk, 100 to 180 ¼ intermediate risk
death were infection in 3 patients, cardiogenic shock in
and <100 ¼ low risk. LVAD ¼ left ventricular assist device.
2 patients, stroke in 2 patients, complication of an unrelated procedure in 2 patients, pulseless electrical
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activity in 2 patients, complication of VT ablation in 1 patient, refractory VT in 1 patient, and trauma
T A B L E 3 Baseline Characteristics and Clinical Outcomes of Validation Cohort
High Risk (n ¼ 20)
in 1 patient. In Kaplan-Meier analysis, transplantation and LVAD-free survival was worse in the high-risk group
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Wider QRS/Larger Scar Predict Worse NICM Survival
Intermediate Risk (n ¼15)
Low Risk
Baseline characteristics 90.0
40.0
13.3
Greater of endocardial or epicardial bipolar scar percentage
16.9 22.1
10.2 7.1
6.3 7.3
trend across groups) (Figure 5). The area under the
QRS duration, ms
141.7 35.6
150.1 32.9
116.9 34.0
risk score receiver operating characteristic curve was
Left ventricular ejection fraction, %
30.6 15.0
28.8 10.8
46.3 10.8
285.5 92.7
136.5 23.2
13.8 58.6 0.0
compared with the intermediate- and low-risk groups (<10% vs. 50% and >80% respectively, p < 0.001 for
0.82 for the validation cohort. A cutoff score of 100 was highly sensitive for development of the primary
Ventricular tachycardia storm, %
EP risk score Clinical outcomes Left ventricular assist device, %
5.0
0.0
endpoint by 3 years (sensitivity 93.5%, specificity
Heart transplantation, %
35.0
6.7
0.0
54.7%), whereas a cutoff of 180 was more specific
Death, %
55.0
40.0
13.3
(sensitivity 64.7%, specificity 85.8%). Values are % or mean SD.
DISCUSSION In particular, unipolar voltage mapping may have In a moderate-sized group of contemporary patients
even greater sensitivity for identifying subtle areas
with NICM presenting for VT ablation, we identified
of abnormality. For example, larger areas of unipolar
wider native QRS duration, greater endocardial or
voltage abnormality were recently shown to predict
epicardial bipolar scar percentage, VT storm, and
irreversibility of NICM in patients without scar
LVEF as independent predictors of shorter time to
detected by MRI or bipolar voltage mapping (16).
death, transplantation, or LVAD. By combining these
In contrast to a recent multicenter report (17), acute
variables into an “electrophysiological risk score,” we
procedural success was not significantly associated
were able to discriminate among patients at high-,
with the primary endpoint in our multivariate model
intermediate-, and low-risk for major adverse events
(p ¼ 0.06). It is likely that with a larger sample size, the
over medium-term follow-up. We subsequently vali-
association would have been statistically significant.
dated the risk score in a separate group of patients
Through the incorporation of electrophysiological
with longer-term follow-up, and it again predicted
risk factors, we aimed to improve risk stratification of
risk with a high degree of accuracy.
patients with NICM beyond LVEF. Should our risk
Whereas left bundle branch block has long been established as a risk factor for adverse heart failure outcomes (13), we further showed that QRS width, within each category of QRS morphology, further pre-
F I G U R E 5 Heart Transplantation- and LVAD-Free Survival in the Validation Cohort by
Risk Group
dicts risk. For example, among those with normal QRS morphology or intraventricular conduction delay, greater QRS width predicted shorter time to death, transplantation, or LVAD. This observation was directionally consistent, although not statistically significant, across all QRS morphology categories. Within a given QRS morphology category, increasing QRS width is likely a manifestation of slower cell-to-cell conduction, potentially a result of increased fibrosis (14). Scar size as assessed by MRI has been shown to predict death and need for heart transplantation among patients with ischemic cardiomyopathy, independently of LVEF (15). More recently, this finding was replicated among patients with NICM (3). Thus, it is not surprising that larger scars, as identified by bipolar voltage mapping, would predict worse prognosis among patients with NICM presenting with VT.
Kaplan-Meier curves are shown for the high-risk, intermediate-risk, and low-risk groups
In fact, careful voltage mapping with good contact
(<10% vs. 50% and >80%, respectively, p < 0.001 for trend across groups). LVAD ¼ left
and sampling density may be a more sensitive tech-
ventricular assist device.
nique than MRI for detection of myocardial scarring.
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Wider QRS/Larger Scar Predict Worse NICM Survival
score be validated in other populations, measurement
predictors of shorter time to death, transplantation,
of QRS duration and voltage mapping could be used as
or LVAD in patients with NICM and VT. By combining
part of a baseline electrophysiological evaluation,
these variables into an electrophysiological risk score,
which, when combined with LVEF, could provide
patients can be classified as high-, intermediate-, or
valuable prognostic information. This information
low-risk for major adverse outcomes.
could then be used to counsel patients and guide the intensity of their heart failure follow-up and in-
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
terventions. Physicians caring for high-risk patients
David S. Frankel, Cardiovascular Division, Electro-
could intensify neurohormonal modulators as aggres-
physiology Section, Hospital of the University of
sively as possible and have a lower threshold for
Pennsylvania, 9 Founders Pavilion, 3400 Spruce
referral to advanced heart failure programs special-
Street, Philadelphia, Pennsylvania 19104. E-mail:
izing in LVAD, transplantation, and other cutting-
[email protected].
edge/experimental treatments. STUDY LIMITATIONS. Although our electrophysio-
logical risk score performed well in this single-center study, it should be validated in other centers. Further, to determine the range of its applicability, the
PERSPECTIVES COMPETENCY IN MEDICAL KNOWLEDGE: In
risk score would also need to be tested in different
addition to LVEF, we identified wider native QRS
patient populations, such as patients with NICM
duration, increased scar percentage detected by
without VT and patients with ischemic cardiomyopa-
electroanatomic mapping, and VT storm as indepen-
thy. Our risk score cannot be calculated in those
dent predictors of shorter time to death, transplan-
without intrinsic atrioventricular conduction, as
tation, or LVAD in patients with nonischemic
native QRS duration is required. Not all patients
cardiomyopathy. We combined these factors to create
underwent epicardial voltage mapping. However, all
an electrophysiological risk score that accurately
patients did undergo endocardial unipolar voltage
divided patients into high-, intermediate-, and low-
mapping, which has been shown to predict the extent
risk categories.
and distribution of midmyocardial and epicardial scar (8). Lastly, the threshold to implant an LVAD or perform a heart transplantation may vary from institution to institution.
TRANSLATIONAL OUTLOOK: Should our risk score be validated in different populations, measurement of QRS duration and voltage mapping could be performed as a baseline electrophysiological evaluation, which, when combined with LVEF, could provide
CONCLUSIONS
more accurate prognostic information. This could then
We identified wider native QRS duration, greater endocardial or epicardial bipolar scar percentage, and
be used to guide the intensity of heart failure followup and interventions.
VT storm, in addition to LVEF, as independent
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KEY WORDS bipolar scar, electroanatomic mapping, heart failure, nonischemic cardiomyopathy, QRS duration
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