Risk stratication in adults with

repaired Tetralogy of Fallot: the long

journey from clinical parameters and
surface ECG to in-depth assessment
of myocardial mechanics, volume and
pressure loading
Stefan Orwat, Gerhard-Paul Diller
This editorial refers to Contemporary
Predictors of Death and Sustained
Ventricular Tachycardia in Patients With
Repaired Tetralogy of Fallot Enrolled in the
INDICATOR Cohort by Valente et al.
1
CHALLENGE OF RISK STRATIFICATION
Tetralogy of Fallot (ToF) is the most
common cyanotic heart defect at birth.
Major advances in cardiac surgery and
paediatric cardiology now enable the vast
majority of patients born with this condi-
tion to survive to adulthood. However,
surgical repair cannot cure these patients
and life expectancy continues to be com-
promised. Haemodynamically relevant
pulmonary regurgitation (PR) is common
and appears to have a major impact on
long-term morbidity and mortality. It
causes RV volume overload eventually
associated with RV dysfunction and isin
itselfassociated with life-threatening
arrhythmias and sudden cardiac death.
While timely pulmonary valve replace-
ment may help to avoid some of the long-
term complications associated with PR,
2
it
appears that merely replacing the pulmon-
ary valve is not sufcient to avoid sudden
death in this young population.
3
As a con-
sequence, numerous researchers have been
struggling to identify reliable risk predic-
tors in ToF patients over the last decades.
This is not an easy undertaking: the het-
erogeneity of the condition combined
with the relatively low annual mortality
rate requires large patient cohorts and
considerable follow-up periods to ensure
sufcient statistical power. In addition,
not all patients die suddenly and
information on the cause of death is not
always available. Not surprisingly, the
number of risk predictors remains there-
fore limited (for an overview of studies,
see table 1): the most prominent and
widely used one is QRS prolongation on
surface ECG. This risk factor is based on
the seminal publication by Gatzoulis et al
4
1.5 decades ago, suggesting a strong asso-
ciation between a QRS duration 180 ms
and poor prognosis. While this association
has been conrmed by other studies, it
appears that improving surgical techni-
ques and trends towards earlier repair
may compromise the prognostic value of
QRS duration or, at least, will shift the
180 ms cut-off to lower values in future.
In addition, a broad QRS complexin
isolationis insufcient to identify indi-
vidual patients with annual event rates
high enough to justify the primary
prophylactic implantation of an implanta-
ble cardioverter-debrillator (ICD).
Subsequently, Khairy et al
5
have proposed
a risk score based on clinical history, QRS
duration, results of ventricular stimulation
and invasive assessment of LV end-
diastolic pressures. Uptake of this risk
score has been mainly hampered by the
fact that invasive pressure measurements
and electrophysiological studies are not
performed routinely for risk assessment in
ToF patients. More recently, the prognos-
tic value of LV dysfunction has been high-
lighted. This is prima facie surprising as
ToF mainly represents a right-sided heart
condition. Nevertheless, ToF patients are
affected by myocardial ischaemia before
corrective surgery that may in part
account for late LV dysfunction.
6
Furthermore, myocardial bres are shared
between the ventricles and ventricular
ventricular interaction
7
may also be
responsible for LV dysfunction in patients
with advanced RV volume overload and
dysfunction. However, systolic LV dys-
function assessed by measuring EF
8
lacks
sensitivity in detecting early LV
dysfunction and is not well suited to iden-
tify ToF patients at risk of death or those
likely to benet from ICD implantation.
Recently, modern myocardial deformation
parameters (such as strain on speckle
tracking analysis) have been increasingly
employed and preliminary studies investi-
gating the utility of these methods for risk
stratication in ToF patients are promis-
ing.
9
Although further conrmation is
required, these parameters seem to be
more sensitive compared with EF in
detecting myocardial damage and their
prognostic values appear to be superior to
that of conventional measures of ventricu-
lar size and function.
ROLE OF CMR
Regarding risk stratication in ToF, until
now, only small, single-centre cardiac
MRI (CMR) studies, employing compos-
ite end points (including symptomatic
deterioration) have been available, not
providing convincing results. Despite its
prominent role in the evaluation of
patients before pulmonary valve replace-
ment,
10
CMR has therefore not gained a
major role for risk stratication in ambu-
latory ToF patients. This may change in
the future. Valente et al present the results
of a large multicentre effort combining
the CMR expertise of four large adult
congenital heart disease centres in North
America and Europe. Using a well-dened
study protocol,
11
the authors assembled
CMR data on 873 ToF patients and inves-
tigated the association between CMR
parameters and outcome. This is an
unusually large number of ToF patients
using a clinically relevant, end point of
death or sustained ventricular tachycardia
(VT). The authors identied LVEF and
RVEF, RV mass-to-volume ratio 0.3 g/mL
and history of atrial tachyarrhythmia as
outcome predictors on multivariate ana-
lysis. Interestingly, VT was rare and con-
rmed sudden cardiac death accounted for
only approx. 14% of deaths. In contrast,
over 50% of patients died due to unknown
or non-cardiac reasons. This limitation
should be considered when applying the
results of the current study directly for risk
stratication of sudden cardiac death in ToF
patients. The study by Valente et al also
highlights the limitations of using EF as a
marker of ventricular dysfunction. Unlike in
patients with acquired heart failure, even
mildly reduced EF was associated with
poor outcome in this study. Therefore, it
appears that EF may be suboptimal in this
setting and more sensitive markers of sub-
clinical ventricular dysfunction are desired
and should be increasingly investigated.
Division of Adult Congenital and Valvular Heart
Disease, Department of Cardiovascular Medicine,
University Hospital Muenster, Muenster, Germany
Correspondence to Dr Stefan Orwat, Division of
Adult Congenital and Valvular Heart Disease,
Department of Cardiovascular Medicine, University
Hospital of Muenster, Albert-Schweitzer-Campus 1; A1,
Muenster 48149, Germany; orwat@uni-muenster.de
Orwat S, et al. Heart February 2014 Vol 100 No 3 185
Editorial
group.bmj.com on September 2, 2014 - Published by heart.bmj.com Downloaded from
RV PRESSURE OVERLOAD-NOT A
BENIGN CONDITION?
One interesting and novel aspect of the
study is the reported association between
elevated RV pressure or RV hypertrophy
and worse outcome. The authors report
that patients who died or experienced an
episode of sustained VT had on average a
RV outow tract (RVOT) gradient of
64 mm Hg and this gradient was signi-
cantly higher compared with the remain-
ing patients investigated with
echocardiography. While the detrimental
impact of PR on RV mechanics and risk of
sudden death
12
has been highlighted, RV
pressure load has received much less
attention. As discussed by the authors, RV
pressure and RV hypertrophy were related
to each other, but provided independent
prognostic information. Therefore, one
could speculate that beyond the obvious
effect of RV pressure overload on RV
hypertrophy, alternative factors such as
inadequate RVadaptation in the setting of
PR may account for this nding. This
interpretation is also supported by the fact
that the correlation between RV pressures
and mass was only modest overall.
Although current guidelines suggest
that interventions for RVOT obstruction
should be considered even in asymptom-
atic patients, the level of evidence is low
(C) and the proposed RVOT pressure gra-
dient necessitating intervention is rela-
tively high.
13
Given the results presented
by Valente et al, this recommendation
may need to be reconsidered. This is espe-
cially true in patients with a RVOT
conduit who may be good candidates for
a percutaneous valve implantation. In
addition, the results of the current study
raise the question whether accepting a
certain degree of RVOT obstruction to
avoid PR is indeed a desirable option,
both at initial surgical repair and during
catheter inventions later in life.
Overall, the current paper by Valente
et al will not solve the problem of accurate
risk stratication in ToF patients but brings
us one step closer to develop a compre-
hensive risk score, now incorporating
CMR data. In addition, the authors have
to be commended, as this study also
serves as a model for how multicentre
efforts can help to overcome the natural
limitations of efforts aiming to risk strat-
ify adult congenital heart disease patients.
Contributors SO and G-PD prepared the draft of the
manuscript; both authors have revised the manuscript
critically for important intellectual content and have
provided nal approval of the manuscript.
Competing interests None.
Provenance and peer review Commissioned;
internally peer reviewed.
To cite Orwat S, Diller G-P. Heart 2014;100:185
187.
Published Online First 29 November 2013
http://dx.doi.org/10.1136/heartjnl-2013-304958
Heart 2014;100:185187.
doi:10.1136/heartjnl-2013-305011
REFERENCES
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Contemporary predictors of death and sustained
ventricular tachycardia in patients with repaired
tetralogy of Fallot enrolled in the INDICATOR cohort.
Heart 2014;100:24753.
2 Therrien J, Siu SC, Harris L, et al. Impact of
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4 Gatzoulis MA, Till JA, Somerville J, et al.
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Table 1 Overview of studies investigating predictors of death or clinically relevant
ventricular arrhythmias in patients with repaired ToF
Author Patients (n) Date of repair Parameters
Katz et al
14
414 19671977 Older age at repair
Presence of a Potts anastomosis
Gatzoulis et al
4
178 19581979 QRS duration
Nollert et al
15
490 19581977 Date of operation (<1970)
Preoperative polycythaemia
Use of RV outflow tract patch
Berul et al
16
101 19801990 QRS duration
Gatzoulis et al
12
793 NA QRS duration, QRS rate of change
Older age at repair
Pulmonary regurgitation (PR)
Ghai et al
8
125 NA Moderate or severe PR
QRS duration 180 ms
Moderate or severe LV syst. dysfunction
Khairy et al
5
252 19852001 Inducible sustained polymorphic VT
Khairy et al
17
121 (selected patient
population with ICD)
NA Prior palliative shunt
Inducible sustained polymorphic VT
QRS duration 180 ms
Ventriculotomy incision
Non-sustained VT
LVEDP 12 mm Hg
Diller et al
9
413 NA QRS duration
Right atrial area
RV fractional area change
LV longitudinal dysfunction
Valente et al
1
873 NA RV hypertrophy
RV and LV dysfunction
Atrial tachyarrhythmias
ICD, implantable cardioverter-defibrillator; LVEDP, LV end-diastolic pressure; ToF, Tetralogy of Fallot; VT, ventricular
tachycardia.
186 Orwat S, et al. Heart February 2014 Vol 100 No 3
Editorial
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15 Nollert G, Fischlein T, Bouterwek S, et al. Long-term
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137483.
16 Berul CI, Hill SL, Geggel RL, et al. Electrocardiographic
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tetralogy of Fallot children. J Cardiovasc Electrophysiol
1997;8:134956.
17 Khairy P, Harris L, Landzberg MJ, et al. Implantable
cardioverter-debrillators in tetralogy of Fallot.
Circulation 2008;117:36370.
Orwat S, et al. Heart February 2014 Vol 100 No 3 187
Editorial
group.bmj.com on September 2, 2014 - Published by heart.bmj.com Downloaded from
doi: 10.1136/heartjnl-2013-305011
2013
2014 100: 185-187 originally published online November 29, Heart

Stefan Orwat and Gerhard-Paul Diller

mechanics, volume and pressure loading

in-depth assessment of myocardial
clinical parameters and surface ECG to
Tetralogy of Fallot: the long journey from
Risk stratification in adults with repaired
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