1. health and fitness
2. disease

Europace (2010) 12, 1156–1175
doi:10.1093/europace/euq261
POSITION PAPER
Heart Rhythm UK position statement on
clinical indications for implantable cardioverter
defibrillators in adult patients with familial
sudden cardiac death syndromes
Clifford J. Garratt (co-chair)1*, Perry Elliott (co-chair)2, Elijah Behr3, A. John Camm3,
Campbell Cowan4, Stephanie Cruickshank5†, Andrew Grace6, Michael J. Griffith7,
Anne Jolly8‡, Pier Lambiase2, Pascal McKeown9, Peter O’Callagan10, Graham Stuart11,
and Hugh Watkins12 (the Heart Rhythm UK Familial Sudden Cardiac Death
Syndromes Statement Development Group)
1
University of Manchester, Manchester, UK; 2University College London, London, UK; 3St George’s Hospital Medical School, London, UK; 4Heart Improvement Programme, UK;
Epsom and St Helier NHS Trust, UK; 6University of Cambridge, Cambridge, UK; 7Queen Elizabeth Hospital, Birmingham, UK; 8SADS, UK; 9Centre for Public Health, Queens
University Belfast, UK; 10University Hospital of Wales, Cardiff, UK; 11Congenital Heart Centre, Bristol Heart Institute, UK; and 12University of Oxford, Oxford, UK
5
Whilst the decision regarding defibrillator implantation in a patient with a familial sudden cardiac death syndrome is likely to be most significant for any particular individual, the clinical decision-making process itself is complex and requires interpretation and extrapolation of
information from a number of different sources. This document provides recommendations for adult patients with the congenital Long
QT syndromes, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, hypertrophic cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy. Although these specific conditions differ in terms of clinical features and prognosis, it is possible and
logical to take an approach to determining a threshold for implantable cardioveter-defibrillator implantation that is common to all of the
familial sudden cardiac death syndromes based on estimates of absolute risk of sudden death.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Sudden cardiac death syndromes † Consensus document † Implantable cardioverter defibrillator
The sudden unexpected death of a young or relatively young person
can have profound implications for the surviving family members
beyond those associated with bereavement and the immediate
sense of loss. Among these other sequelae may be a concern that
the sudden death was caused by a genetic condition and that
other family members may suffer the same fate. This increased
awareness of the role of inherited conditions in the development
of malignant ventricular arrhythmias and sudden death of young individuals has been accompanied by widespread acceptance of the
implantable cardioverter defibrillator (ICD) as an important potential means of preventing sudden death in these circumstances.
Although the decision regarding defibrillator implantation is likely
to be one of the most significant for any particular individual, the
clinical decision-making process itself is complex and requires
interpretation and extrapolation of information from a number of
different sources. The relative rarity of the individual conditions
seriously limits the amount and quality of the data upon which the
clinician can draw in making a recommendation. It is not unusual
for different members of the same family to receive different recommendations regarding ICD therapy from their (different) respective cardiologists despite little or no difference in their clinical
circumstances. Patients can find this situation both difficult to
* Corresponding author. C.J. Garratt, Manchester Heart Centre, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK. Tel: +44 161 276 8858; fax: +44 161
2764907, Email: clifford.garratt@cmmc.nhs.uk
†Nursing representative
‡Patients’ representative
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2010. For permissions please email: journals.permissions@oxfordjournals.org.
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Received 18 January 2010; accepted after revision 11 June 2010
1157
HRUK position statement
understand and frustrating. International and national clinical guidelines have an important role in this process. The purpose of the
current document is to focus particularly on the indications for
ICD implantation in adult patients (16 years and over) with the familial sudden death syndromes, specifically the ion channelopathies
[long QT syndromes (LQTS), Brugada syndrome, catecholaminergic
polymorphic ventricular tachycardia (CPVT)], hypertrophic cardiomyopathy (HCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC). All patients with (or suspected of having) one of
these familial sudden cardiac death (SCD) syndromes should be
assessed by a clinician with considerable experience in the management of these conditions. This document does not aim to provide
recommendations for ICD implantation for children with these
syndromes.
The ACC/AHA/ESC 2006
guidelines for the management
of patients with ventricular
arrhythmias and the prevention
of sudden cardiac death
(i) The decision to recommend implantation of an ICD is dependent upon a balance between perceived risks of sudden death
in an individual patient (often expressed in terms of per cent
risk of death/year) and the morbidity/mortality associated
with lifelong ICD therapy, which is not easy to quantify.
A survey of UK electrophysiologists was undertaken to
examine an overall threshold for ICD implantation in terms
of percentage risk of sudden death per year. We postulated
that heart rhythm specialists with the experience of ICD
implantation and follow-up would be well placed to put the
risks of ICDs in context, particularly if they were to imagine
themselves in the position of the patient. The following question was emailed to 71 electrophysiologists/ICD implanters in
the UK: ‘If you personally had a cardiac condition with a quantifiable risk of sudden death, and the only treatment was an
ICD, what level of risk (in terms of percentage risk of death/
year) would prompt you to have an ICD implanted? The question refers to your current age and it is assumed that this level
of risk remains constant with time.’ Of the 50 respondents, the
most common response (42% of respondents) received
regarding the ICD threshold was 1% risk of sudden death/year,
with a mean value of 2.47%/year. Implanters .45 years had a
significantly higher threshold for implantation (3.06 + 1.38%/
year) than younger implanters (1.64 + 1.08%/year, P , 0.05).
(ii) Consensus process. A statement development group was
selected by the Council of Heart Rhythm UK, consisting of
cardiac electrophysiologists, cardiac nurses, patient representatives, and specialists in heart muscle disease. An initial meeting
of the group was held at which the need for a specific document
addressing a unified approach to ICD implantation in the familial
SCD syndromes was agreed and the results of the survey of UK
implanters regarding thresholds for ICD implantation were presented. Subsequently, a comprehensive review of evidence in
English language publications relating to diagnostic criteria, risk
assessment, and ICD implantation in the syndromes was undertaken by specified group members. Specific attention was directed
to studies in which absolute risks of sudden death (rather than
relative risks of cardiac events) were quoted or could be calculated. A draft document was produced according to a prespecified format common to the individual conditions addressed.
The congenital long
QT syndromes
The congenital LQTS are caused by genetically determined disturbances of ion channel function leading to prolonged repolarization in ventricular myocytes.2 – 4 LQT1 is caused by mutations in
the gene KCNQ1,5 which encodes for the potassium channel
that, when co-expressed with other subunits, produces the IKs
current. LQT2 is caused by mutations in KCNH2,6 the gene encoding the potassium channel that carries the IKr current. Mutations in
the cardiac sodium channel gene SCN5A 7 cause LQT3. Although a
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The ACC/AHA/ESC guidelines (2006)1 reflect a consensus of international expert opinion on the management of patients with ventricular arrhythmias and others considered at risk of sudden death.
Specific sections of this document address ventricular arrhythmias
associated with ‘genetic arrhythmia syndromes’ and cardiomyopathies. These guidelines are intended to assist health care providers
in clinical decision-making by ‘describing a range of generally acceptable approaches for the diagnosis and management of specific diseases or conditions.’ They attempt to ‘define practices that meet
the needs of most patients in most circumstances.’
With regard to ICD implantation in the familial sudden death
syndromes, the recommendations are very broad in terms of
what can be considered acceptable practice. For instance, class I
indications (ICDs definitely indicated) are largely restricted to
patients who have already demonstrated a propensity for malignant ventricular arrhythmias or sudden death. No class III indications (ICDs contraindicated) are suggested by these guidelines.
As a consequence, the 2006 guidelines reflect the uncertainties
and broad range of current clinical practice internationally. In the
current document, we aim to provide a more detailed discussion
of the approach to clinical decision-making regarding ICD implantation in the adult patient population, with an emphasis on (i)
establishing a correct clinical diagnosis, (ii) assessment of absolute
risk of sudden death within specific clinical and genetic subgroups
where possible, and (iii) published experience of ICDs in these
patients. Details of molecular genetics, pathophysiology, and
wider management aspects are not described in detail but are discussed where necessary in order to put the issues relevant to ICD
implantation in perspective. The specific recommendations in this
document are based on a unified consensus-based approach to
determining appropriate thresholds for ICD implantation across
the range of familial SCD syndromes. The target users of this position statement include all healthcare professionals involved in the
management of this group of patients.
Development of the position
statement
1158
number of rarer forms of the syndrome exist, LQT 1, 2, and 3
comprise the majority of genotyped patients.8,9
Current ACC/AHA/ESC guidelines for
implantable cardioverter defibrillator
prescription in long QT syndromes
The classes of ICD indications as defined by the ACC/AHA/ESC
Writing Committee can be summarized as follows and refer to
individuals who otherwise have reasonable expectation of survival
with a good functional status for .1 year.
Class I. Implantation of an ICD along with the use of betablockers is recommended for LQTS patients with previous
cardiac arrest (level of evidence: A).
Class IIa. Implantation of an ICD with continued use of betablockers can be effective to reduce SCD in LQTS patients
experiencing syncope and/or VT while receiving beta-blockers
(level of evidence: B).
Class IIb. Implantation of an ICD with the use of beta-blockers
may be considered for prophylaxis of SCD for patients in categories possibly associated with higher risk of cardiac arrest
such as LQT2 and LQT3 (level of evidence: B).
Classical findings
The classical clinical presentation of the condition is with syncope
or cardiac arrest in a child or adolescent, associated with a family
history of similar presentations and with a prolonged QT interval
on the surface electrocardiogram (ECG). The original syndrome
described by Jervell and Lange-Neilsen is associated with congenital deafness (autosomal recessive), with the autosomal dominant
form (Romano-Ward) being associated with normal hearing. Triggers for syncope/cardiac arrest differ in the three commonest
forms of autosomal dominant disease. In LQT1, cardiac events
occur typically in the setting of physical exertion, including swimming. LQT2 arrhythmias are classically associated with sudden
auditory stimuli like alarm bells and telephone rings. LQT3 is
best known for death or syncope during sleep.
Electrocardiographic features
The typical electrocardiographic features of severely affected individuals include marked prolongation of the QT interval (often in
excess of 500 ms) and significant T wave abnormalities including
T wave alternans and intermittent marked T wave inversion.
Since the advent of genetic testing, it has become clear that characteristic T wave shapes correlate with specific genotypes although
there is considerable overlap. Patients with LQT1 tend to have a
broad and pronounced T wave or late onset of a normal appearing
T wave. Patients with LQT2 have low-amplitude T waves or bifid
T waves and those with LQT3 have the latest appearing T waves
that are peaked and/or bifid or are asymmetrical with a steep
downslope.
Lesser degrees of QT prolongation
It is increasingly acknowledged that, in addition to the classical
presentation, symptomatic individuals may present with lesser
degrees of QT prolongation or even borderline or normal
corrected QT intervals. The QT interval is defined as the interval
from the onset of the QRS complex to the point at which the
T wave ends.10 When the QT interval is measured in individual
leads, the lead showing the longest QT should be used (usually
V2 or V3). However, if this measurement differs by .40 ms
from that in other leads, the measurement may be in error and
measurements from adjacent leads should be considered. The
QT interval is considered prolonged when it exceeds 450 ms in
males and 460 ms in females following correction for heart
rate.10 Many medications and other cardiac conditions can give
rise to prolonged QT intervals and this should be taken into consideration when the diagnosis of congenital LQTS is being suggerted. Some authors recommend the use of provocative
epinephrine tests11 if the syndrome is suspected but the QT interval or normal or borderline. These provocative tests have been
evaluated only in selected subgroups, however, and are not foolproof even in these groups. The decision to perform epinephrine
provocative testing should be taken in the context of the clinical
and family history and the likely effect on patient management
that would result from a ‘positive’ or ‘negative’ result; currently
they are not recommended as part of routine clinical practice.12
Conventional electrophysiological testing does not have a role in
the diagnosis of LQTS.
Genetic testing
The advent of genetic testing for mutations associated with the
congenital LQTS has raised the possibility of a “genetic diagnosis”
for suspected cases.13 Although the specificity of a positive result is
very high, the diagnostic yield (sensitivity) of current genetic testing
is relatively modest. In patients with classical clinical presentations,
the pick-up rate varies between 70 and 90% (depending upon the
laboratory involved) but in patients with borderline QT interval
prolongation, the diagnostic yield is significantly less than this,
perhaps 20 –30%. For this reason, and the fact that a ‘negative’
result does not exclude the diagnosis, widespread genetic testing
of individuals presenting with normal/borderline QT intervals, no
other clinical features and no family history of the syndrome has
a very limited role as a means of diagnosis.
Risk of sudden death within specific
clinical and genetic subgroups
The overall population based-risk of the LQTS with expressed
phenotypic evidence of disease is low14 when receiving appropriate treatment most usually with beta-blockers.15 Evidence from
the international LQT registry indicates an 4% risk of mortality
over 40 years,14,16 i.e. 0.1%/year and this observation is further
supported by their most recent data.17
Indicators of high relative risk of sudden death include a personal
history of aborted SCD or syncope and QT prolongation
.500 ms. Recent syncope (within the last 2 years) is a stronger
predictor of aborted cardiac arrest/death than is a more remote
history of syncope.17 Gender and age also play significant roles
in influencing the clinical course of LQTS in that cardiac events
tend to occur more frequently in children, with males having an
increased risk of events during pre-adolescence and females
having higher event rates in adolescence and beyond.18 Although
it is often assumed that sudden death of a sibling is a risk factor
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Establishing a clinical diagnosis
C.J. Garratt et al.
HRUK position statement
for death in LQTS patients, there is little evidence to support this.
Kaufman et al. 19 have specifically examined this question among
relatives of probands entered into the International Long QT Registry between 1979 and 2006. Clinical and ECG criteria were
obtained at enrolment and updated annually. Of the 1915 subjects,
there were 270 who had a sibling who had died. In a multivariate
analysis, QTc .0.53 s and a personal history of syncope were
associated with an increased risk of aborted cardiac arrest or
death but death of a sibling was not. The authors concluded that
severe symptoms in a close relative cannot be used as an indicator
of personal risk for those family members affected by the same
pathogenic substrate; rather, that incomplete penetrance and variable expressivity that are such consistent findings in LQTS preclude predicting severity of symptoms even in siblings. In
contrast, an individual’s own QTc and history of syncope were
strong predictors of risk. Unusually for a study of this type, the
authors also examined absolute risk of aborted cardiac arrest/
death for asymptomatic individuals on beta-blockade who had
had a sibling die. No aborted cardiac arrest/deaths occurred in
50 such individuals over a 5-year period.
Patients presenting with syncope despite beta-blockade
The same study20 also described a historical control group consisting of LQTS patients with continuing syncope despite betablockade. Eleven of 72 patients died or had recurrent cardiac
arrest during a 7-year follow-up, i.e. 2.18%/year.
Although the same reservations regarding the retrospective
nature of this and similar studies still apply,21 given the likely high
absolute risk of sudden death in this patient group, ICD implantation is certainly a reasonable approach. It is important to recognize however that left cardiac sympathetic denervation (LCSD) is
an underused option and should be considered in patients with
syncopal symptoms persisting despite full beta-blockade, those
with asthma or other intolerance of beta-blockers, and those
with shocks who already have an ICD in place. Left cardiac sympathetic denervation is associated with significant reduction in
the incidence of aborted cardiac arrest and syncope in high-risk
LQTS patients, although it does not confer complete protection.23
Although this procedure, either via a video-assisted thoracoscopic
procedure24,25 or using the traditional surgical approach, cannot
completely abolish the risk of subsequent arrhythmic events and
sudden death, it does offer a reasonable alternative to ICD particularly in the paediatric population when the co-morbidity associated
with ICD treatment can be high.26
In terms of beta-blocker therapy, the particular agent may well
be relevant in terms of efficacy in the LQTS, with many clinicians
preferring propranolol or nadolol based on the long-term experience with these agents that block both beta-1 and beta-2 adrenergic receptors.27 The European experience indicates success with
these drugs when properly used, leading to low residual SCD
rates.15,28 Available data from numerous studies indicate excellent
symptom suppression and almost zero mortality in LQT1 patients
treated with these drugs long-term,15,28 non-compliance and the
use of QT-prolonging drugs being responsible for almost all lifethreatening ‘beta-blocker failures’.22
LQT2 patients are also best treated with beta-blockers as the
first line of management. In this group, syncope suppression is
not so good as in LQT1 but the Italian experience would again
suggest an excellent impact on prognosis.15 Recent data taken
from adolescents from the International LQT registry would also
support that view.17
LQT3 patients have mutations in SCN5A and are relatively
uncommon7 with less published experience of the outcome
when treated with beta-blockers.15 LQT3 patients are less likely
to present with warning symptoms, with the first event potentially
being SCD and this may have provoked the concern physicians
express in the management of these patients.14 More recent
reports of the outcome of LQT3 patients29 suggest that although
infants who suffer cardiac events during their first year of life suffer
from a highly malignant form of the disease, most LQT3 patients
can do well and for a long period of time with the current therapies. Beta-blockers will often be prescribed in the first instance
before the genotype is available unless the clinician is absolutely
certain regarding an LQT3 diagnosis based on the ECG. It seems
likely that beta-blockers will remain the initial treatment for
many LQT3 patients and there is evidence that LCSD can be
very effective in their management.29 Potentially valuable (but
unproven) drug options such as flecainide, mexiletine, and
calcium channel blockers are likely to be reserved for patients
with ICDs in situ and continuing symptoms.
Recommendation: Long QT syndrome patients experiencing
continuing syncope despite beta-blockade or LCSD (when VT/
VF has not been excluded as the cause of syncope) should
undergo ICD implantation.
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Patients presenting with aborted cardiac arrest
Although there are no prospective studies available on the risk of
recurrent cardiac arrest in LQTS patients presenting with aborted
sudden death and not treated with ICDs, such individuals are
thought very likely to suffer subsequent events and it is for this
reason that this form of presentation is considered an AHA/
ACC/ESC class 1 indication for ICD implantation. Zareba et al. 20
described a group of such patients, used as historical controls
for comparison with a matched group undergoing ICD implantation. Twenty-seven of 89 patients died or had recurrent
cardiac arrest during a 9-year follow-up, i.e. an absolute risk of
death of 3.37%/year. As a consequence of the retrospective
nature of the data collection in this study,21 it is likely that this
figure represents an upper estimate of the true risk of sudden
death in these patients. Many of the ‘controls’ died within the
first month after identification, suggesting that they may have
died as a result of complications of the original cardiac arrest
and that their deaths may not have been sudden or preventable
by ICD therapy. Indeed more recent studies22 suggest that outcomes of LQTS patients presenting with cardiac arrest maybe
good if appropriately treated with beta-blockade. Nevertheless,
in LQTS patients presenting with aborted cardiac arrest, the consequences of a recurrence of malignant ventricular arrhythmias
(for instance due to drug non-compliance or other reason) are
such that ICD implantation is recommended in this group.
Recommendation: Long QT syndrome patients presenting with
ventricular fibrillation/cardiac arrest without reversible precipitant
should undergo ICD implantation in addition to oral beta-blockade
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Patients without symptoms
Priori et al. 30 examined lifetime cardiac event rates (syncope and
sudden death) in initially asymptomatic patients. There were statistically significant differences in the rates of cardiac events and
cardiac arrest/sudden death depending on the underlying genotype, with patients with LQT2 or LQT3 having a higher risk than
those with LQT1; hence the class IIb indication for ICD implantation in the ACC/AHA/ESC guidelines (LQT2 or LQT3). With
regard to the key endpoint of SCD, absolute event rates according
to genotype were as follows:
LQT1 0.3%/year (males 0.33%, females 0.28%);
LQT2 0.6%/year (males 0.46%, females 0.82%);
LQT3 0.56%/year (males 0.96%, females 0.30%).
Electrophysiological studies
Conventional invasive electrophysiological testing using programmed stimulation protocols designed for other applications is
not helpful in terms of defining the risk of SCD.34 There may be
a role for invasive phenotyping35 although prospective evidence
of benefit is needed.
Brugada syndrome
The Brugada syndrome is an inherited condition that is characterized by ventricular arrhythmias, syncope, or sudden death in the
presence of a specific ECG pattern: coved ST elevation and
J-point elevation of at least 2 mm in at least two of the right precordial ECG leads in the absence of cardiac structural disease.36,37
Altered function of the ion currents ITO, ICa2+, or INa+ are thought
to be possible mechanisms for this syndrome. To date, the great
majority of identified disease-causing mutations have been
located in the SCN5A gene encoding the alpha subunit of the
human voltage-gated sodium channel.
Current ACC/AHA/ESC guidelines for
implantable cardioverter defibrillator
prescription in Brugada syndrome
The classes of ICD indications as defined by the ACC/AHA/ESC
Writing Committee can be summarized as follows and refer to
individuals who otherwise have reasonable expectation of survival
with a good functional status for .1 year.
Class I. An ICD is indicated for Brugada syndrome patients
with previous cardiac arrest.
Class IIa. An ICD is reasonable for Brugada syndrome patients
with spontaneous ST segment elevation in V1, V2, or V3 who
have had syncope; an ICD is reasonable for Brugada syndrome
patients with documented VT that has not resulted in cardiac
arrest.
Class IIb. EP testing may be considered for risk stratification in
asymptomatic Brugada syndrome patients with spontaneous ST
elevation.
Establishing a clinical diagnosis
The diagnosis of the syndrome in an individual requires the presence of the type 1 Brugada ECG pattern with at least one of the
other recognized diagnostic criteria from the 2005 consensus
document37: syncope, prior cardiac arrest, documented or inducible polymorphic ventricular tachycardia or ventricular fibrillation, a
family history of sudden death ,45 years old, or nocturnal agonal
respiration. As part of the diagnostic process, it is important to
exclude other conditions that may mimic the Brugada ECG
pattern. These include structural disease that may be hereditary
(ARVC) or acquired (for example, acute myocardial infarction or
ischaemia of the right heart or pulmonary embolism) and similar
ECG patterns in normal hearts (early repolarization syndrome or
hypothermia). These are separate clinical entities and have different pathophysiologies and prognoses.37
The ECG pattern can be dynamic and therefore intermittently
present. In some cases, the ECG pattern may be associated with
fever, electrolyte abnormality, or drug exposure. It can also be
incompletely expressed in a family. Known or suspected mutation
carriers can have a normal ECG or a non-diagnostic Brugada
pattern of a saddle-shaped ST segment with or without elevation:
the type 2 and 3 ECG patterns, respectively. In these cases, a diagnostic challenge with a sodium channel blocker such as ajmaline,
flecainide, pilsicainide, propafenone, and procainamide may
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So with regard to asymptomatic patients even with the highest risk
genotype, risk of death was ,1%/year, suggesting that the indication for ICD implantation is not particularly strong in any of
these groups. The reported risk in a study looking at beta-blockers
in different genotypes would also support a good prognosis with
four sudden deaths occurring in an average 5-year follow-up in
335 patients.15 These data do not support the current class IIb recommendation for ICD implantation in asymptomatic individuals
based purely on genotype.
If one were to try and identify specific high-risk features among
asymptomatic patients with LQTS, then QT duration would seem
a much better candidate than genotype. The major factor contributing to an increased risk of cardiac events (syncope, aborted
cardiac arrest, or LQTS-related death) during childhood or adolescence is a QTc interval .500 ms.12,31,32 Sauer et al. 33 studied
adults presenting after age 18 in the International Long QT Syndrome Registry and looked at aborted cardiac arrest/LQTS
death, endpoints particularly relevant to ICD therapy. Potential
lethality of LQTS in adulthood, measured by aborted cardiac
arrest or LQTS-related sudden death was related to female
gender, QT duration .500 ms, and interim syncope after age
18. These all supercede genotype in terms of predictive
power.29,33 QTc was particularly relevant, with a QTc of 500–
549 ms (vs. ,499 ms) associated with an HR of 3.34, and a QTc
interval of .550 ms (vs. ,499) contributed an HR of 6.35. Moreover, any QTc interval ,499 ms was found not to contribute independently to an increased risk of a lethal event (compared with a
QTc interval ,439 ms).These risk factors held true for asymptomatic as well as symptomatic patients. The frequency of ACA
before age 18 and the frequency of ACA/LQTS-related death
after age 18 were similar among the three genotypes.
Recommendation: The identification of an LQT2 or LQT3 genotype should not by itself constitute an indication for ICD
implantation
C.J. Garratt et al.
1161
HRUK position statement
induce the typical type 1 ECG pattern and support the diagnosis in
a family member.37
It has become apparent that sporadic cases of type 1 ECGs
without a family history or other diagnostic features of the condition may occur, some being revealed by exposure to drugs
with sodium channel-blocking effects. Only a small proportion of
these drug-induced cases are associated with ventricular arrhythmias and could hence be described as the Brugada syndrome.38,39
It is not clear whether these sporadic cases have an underlying
genetic predisposition, and whether they represent latent
Brugada syndrome has not been clearly established.
Genetic testing
Genetic testing has a very low sensitivity for the Brugada syndrome, with a ‘positive’ test being found in only 30% of those
with clear evidence of the clinical syndrome. As a consequence,
the value of genetic testing for diagnostic purposes is limited.
Risk of sudden death within specific
clinical and genetic subgroups
Patients presenting with aborted cardiac arrest
Table 1 describes these data according to patient presentations
with the diagnostic type 1 Brugada ECG and sudden death rates
Patients presenting with syncope
Absolute rates of potentially lethal events are also high in Brugada
patients presenting with syncope (Table 1) and are very similar to
those associated with LQTS patients experiencing syncope despite
beta-blockade; all studies show rates considerably higher than
1%/year.
Recommendation: Brugada syndrome patients with syncope
(when VT/VF has not been excluded as the cause of syncope)
should undergo ICD implantation.
Spontaneous type 1 electrocardiogram in the absence of
symptoms
There is considerable controversy concerning the management of the
asymptomatic Brugada syndrome with a spontaneous type 1 ECG
abnormality. In a subgroup analysis of a larger series, Brugada
et al. 41,42 reported event rates in 547 patients who had not suffered
a previous cardiac arrest, 423 (77%) of whom were asymptomatic
and 55% of whom had a family history of SCD. The overall risk of
sudden death or ventricular fibrillation was 8% over 24 + 32
months of follow-up (4% per year) and this was greatest among
individuals with spontaneous type 1 ECG patterns, syncope, and sustained ventricular arrhythmia inducible at EP studies. Asymptomatic
carriers with and without spontaneous ECG abnormalities were
also found to be at higher risk if they were inducible at EPS.
Contemporaneously, Priori et al. 45 had published a cohort of
200 patients with a longer mean follow-up time (34 + 44
months) in which EP studies had a low positive predictive value
for cardiac events and sudden death. Patients with spontaneous
ECG abnormalities and syncope were at highest risk (hazard
ratio 6.4). Those without syncope but a spontaneous type 1
ECG pattern (41%) were at an intermediate risk (hazard ratio
2.1), whereas a negative baseline ECG, with or without syncope,
was considered low risk.
Table 1 Cardiac event rates per annum from different study populations for different clinical presentations of Brugada
syndrome calculated from available data
Brugada et al. 41
Sacher et al. 50
Takagi et al. 49
Sarkozy et al. 51
Probst et al. 48
Total patient numbers
334
220
188
47
1029
Prior cardiac arrest
13.8%
10.7%
9.8%
Not studied
7.7%
Previous syncope
Asymptomatic
8.8%
(72% FH) 3.74%
3.15%
(54% FH) 1.7%
1.9%
(10% FH) 0%
2.9%
(57% FH) 4.8%
1.9%
(37% FH ) 0.5%
Asymptomatic spontaneous type 1 ECG
6.4%
2.54%
0%
Unavailable
0.81%
Asymptomatic drug-induced type 1 ECG
0%
0.73%
0%
Unavailable
0.35%
...............................................................................................................................................................................
Event rates are rates per annum of sudden cardiac death, ventricular fibrillation, or (in patients with ICDs) appropriate shocks per annum.
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The understanding of the risk of sudden death in the Brugada syndrome has been informed by reports from a few different series of
patients. The Brugada group, who originally described the syndrome
in 1992, hold a registry with a large number of individuals collected
from across Europe and the USA.36,40 – 43 There are other separate
cohorts from an Italian group led by Priori et al.,44,45 a joint European
venture led by Wilde and Eckardt and colleagues46 – 48 and the Japan
Idiopathic Ventricular Fibrillation Study Investigators.49 FrancoJapanese50 and Belgian51 groups have reported their experiences
of ICD implantation in Brugada syndrome, the latter for primary prevention and from the Brugada group.
Indicators of high relative risk of sudden death associated with
the syndrome include a personal history of aborted SCD or
syncope (RR 3.51), the spontaneous presence of a type 1 ECG
pattern (as opposed to a drug-induced type 1 pattern) (RR4.65),
male gender (RR 3.47), and South-East Asian origin. A family
history of sudden death and SCN5A mutation status do not carry
an increased risk of sudden death.
or appropriate ICD shock rates. Despite some variation in terms
of absolute rates of SCD, it is clear that patients presenting with
the Brugada ECG and aborted cardiac arrest have a very high
risk of subsequent similar events and there is widespread agreement that an ICD is indicated in these patients.
Recommendation: Brugada syndrome patients presenting with
ventricular fibrillation/cardiac arrest without reversible precipitant
should undergo ICD implantation.
1162
Asymptomatic patients who require drug-provocation to
reveal the Brugada pattern
In contrast to the controversy discussed above, there is widespread agreement that asymptomatic patients who require drugprovocation to reveal the Brugada pattern are at very low risk of
sudden death (Table 1).
Recommendation: Asymptomatic individuals who require a drug
to induce the type 1 ECG pattern are at low risk of sudden death
and the risks of ICD therapy are likely to outweigh the benefits in
this group.
Catecholaminergic polymorphic
ventricular tachycardia
Catecholaminergic polymorphic VT is an uncommon arrhythmogenic disorder characterized by life-threatening ventricular
arrhythmias associated with physical or emotional stress in the
absence of structural heart disease.58 – 60 The autosomal dominant
form is caused (in up to 60% of cases) by mutations in the cardiac
ryanodine receptor gene RyR2.61,62 This gene encodes the cardiac
ryanodine receptor, the major calcium release channel on the sarcoplasmic reticulum in cardiac myocytes. A rarer autosomal recessive form has been found to be associated with mutations in the
cardiac calsequestrin gene CASQ2, which encodes the SR Ca2+binding buffer protein CASQ2.63 It is thought that the resulting
defective calcium handling predisposes to malignant ventricular
arrhythmias via delayed afterdepolarization-induced extrasystolic
activity under conditions of exercise or other catecholaminergic
stimulus.64
Current ACC/AHA/ESC guidelines for
implantable cardioverter defibrillator
prescription in catecholaminergic
polymorphic ventricular tachycardia
The classes of ICD indications as defined by the ACC/AHA/ESC
Writing Committee can be summarized as follows and refer to
individuals who otherwise have reasonable expectation of survival
with a good functional status for .1 year.
Class I. Implantation of an ICD along with the use of betablockers is recommended for patients with CPVT who are survivors of cardiac arrest (level of evidence C).
Class IIa. Implantation of an ICD along with the use of betablockers can be effective for affected patients with CPVT with
syncope and/or documented sustained VT while receiving betablockers (level of evidence C).
Establishing a clinical diagnosis
Classical features
Patients are usually children, adolescents, or young adults presenting with syncope due to bidirectional ventricular tachycardia
(beat-to-beat alternation of the QRS axis), polymorphic ventricular
tachycardia, or idiopathic ventricular fibrillation occurring during
physical exercise or emotion.65 There may be a family history of
sudden death at an early age, and extensive investigation usually
reveals no evidence of structural heart disease.
Electrocardiographic features
The resting ECG is usually normal or shows sinus bradycardia, and
these patients not infrequently are given a diagnosis of ‘LQTS with
normal QT’. Exercise electrocardiography or intravenous catecholamine infusion is the key investigation in terms of clinical diagnosis,
with a high yield of exercise-induced ventricular salvos in this condition. Ambulatory electrocardiography can also play a role in identifying exercise-induced ventricular arrhythmias as a cause of
symptoms, although in less controlled circumstances. Although
exercise-induced bidirectional VT has been considered the hallmark of this condition, this arrhythmia has been known to occur
occasionally in other channelopathies such as Andersen syndrome
and LQTS. In the latter conditions, however, the resting ECG is
very likely to show QT and TU abnormalities.
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This conflict has been repeated when the other studies in
Table 1, apart from Sarkozy et al.,51 are compared with the
Brugada group data. They have generally demonstrated lower
event rates, particularly among asymptomatic individuals, a lower
proportion of individuals with a family history of SCD, possibly
indicating less penetrant and therefore less severe disease, and a
failure of positive predictive value for EP studies, probably
because of the lower event rate. The argument has focused on
two main characteristics of the cohorts being studied: whether
Brugada syndrome had been sufficiently and accurately diagnosed
on the basis of the presence of type 1 ECGs in the non-Brugada
series; and whether the Brugada registry was subject to a referral
bias towards more severe cases, a trend commonly seen in early
registry data for many relatively uncommon conditions.52 – 54
The publication of two meta-analyses has informed the debate
further regarding the role of electrophysiology.55,56 In both
meta-analyses, a discrepancy was detected between the Brugada
series and other studies, with little positive predictive value being
found by the latter group. It was suggested that the early referrals
to the registry, ‘the founders’ effect’ may be causing selection
bias.54 There was agreement however concerning the high negative
predictive value of EPS in asymptomatic patients, which is consistent whether the higher risk Brugada series is considered or the
other studies described by Paul et al. 56
The controversy over the role of EPS may be resolved by
further systematic long-term prospective studies in the USA and
Europe. In the meantime, there are methodological concerns
about EP studies: the greater inducibility of Brugada syndrome
patients compared with normal individuals; the ‘false positive
rate’ in normal subjects; the reproducibility of findings; and the relevance to a dynamic and varying substrate.46,57 In summary, the
value of EP studies to predict sudden death in asymptomatic
patients is unclear and unresolved. They may provide some reassurance if negative in asymptomatic patients, but the risk of inconclusive positive results must be appreciated.
A firm recommendation regarding ICD implantation in this group
(spontaneous type 1 ECG without symptoms) cannot be made at
this time; either a conservative strategy or ICD implantation based
on results of EP testing can be supported by different series.
C.J. Garratt et al.
HRUK position statement
Genetic tests
Although the diagnostic yield (sensitivity) from genetic testing is
relatively high (80%66) in patients with typical clinical features,
a negative test does not exclude the diagnosis. A positive genetic
test is of great value for the individual patient given the prognostic
implications and for screening family members.
Electrophysiology studies
Electrophysiology studies have a low sensitivity and specificity for
inducing ‘clinical’ arrhythmias in patients with CPVT, with or
without catecholamine infusion.65
Risk of sudden death within specific
clinical and genetic subgroups
a device. Defibrillator shocks have the potential to trigger a ventricular arrhythmia ‘storm’ in these patients secondary to a pain- and
anxiety-induced catecholamine surge. Failures of the ICD to
prevent ventricular arrhythmia-related deaths have been reported
under these circumstances.69
Patients with CPVT are at higher risk in the absence of betablockade, with a 3.1%/year risk of fatal or near-fatal events under
these circumstances.66 As with LQTS, other options exist if betablockade cannot be tolerated. Initial experience with LCSD in
patients with CPVT has been encouraging70 and provides a
logical form of treatment for patients with this condition who
are unable to take full dose-beta blockade or continue to have
symptoms despite medication.
Patients presenting with aborted cardiac arrest
There are no data available on the absolute risk of death in patients
with CPVT presenting with aborted cardiac arrest, although this
presentation has been shown to be an independent predictor for
subsequent fatal or near-fatal events66 in an overall population
that carries a 1.2% per year risk of death on beta-blockade. As a
consequence, it is very likely that the risk/benefit equation in this
group favours ICD implantation. Conversely, patients presenting
with syncope rather than aborted cardiac arrest did not have a
higher fatal or near-fatal event rate during follow-up.
Recommendation: Catecholaminergic polymorphic ventricular
tachycardia patients presenting with ventricular fibrillation/cardiac
arrest without reversible precipitant should undergo ICD implantation in addition to oral beta-blockade or LCSD.
Patients with documented sustained VT or syncope
despite beta-blockade and/or left cardiac sympathetic
denervation
The absolute risk of CPVT patients with syncope despite betablockade (or after LCSD) is unknown but clearly additional treatment will be required under these circumstances. Some preliminary studies have suggested beneficial effects of other drugs such
as flecainide71 or verapamil but certainly ICD treatment should
be considered in these cases.
Recommendation: Catecholaminergic polymorphic ventricular
tachycardia patients experiencing sustained VT or syncope (when
VT/VF has not been excluded as the cause) despite beta-blockade
or LCSD should be considered for ICD implantation.
In contrast to the LQTS, in CPVT there is an opportunity to test
the efficacy of beta-blockade to prevent malignant ventricular
arrhythmias by means of provocative testing (exercise electrocardiography or catecholamine infusion). Some authors have indicated
that beta-blockade should be titrated in order to ensure a
maximum sinus rate on exercise of 110 bpm, based on effectiveness in suppressing ventricular arrhythmias. Results of exercise
stress tests during follow-up are significantly associated with
future cardiac events,66 but sensitivity and specificity of the test
are not high.
Recommendation: Catecholaminergic polymorphic ventricular
tachycardia patients experiencing exercise-induced sustained VT
despite beta-blockade or LCSD should be considered for ICD
implantation.
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The recent discovery and relative rarity of CPVT is such that the
available evidence concerning risk of SCD is based on considerable
fewer patients than either LQTS or the Brugada syndrome and
absolute risks of sudden death in clinical subgroups are much
less well-defined.
It is said that high lethality is a particular feature of both RyR2
CPVT and non-genotyped CPVT and that the protection afforded
by beta-blockade is less than in the LQTS.65,66 This is difficult to
measure in any objective way given that CPVT is a much more
recently discovered condition and, as has been the case for
LQTS, Brugada syndrome and HCM, it is likely that lethality will
be overestimated if based on initial series comprising the most
severely affected individuals. Nevertheless, the fact that in the
largest study of CPVT patients reported to date66 the fatal/nearfatal event rate was as high in family members as in probands
does support the possibility that gene mutations in this condition
are highly penetrant.
As a consequence, oral beta-blockade (1 to 2 mg/kg per day
nadolol, 3 to 4 mg/kg per day propranolol) is recommended
for all mutation carriers even in the absence of symptoms.
There have been a number of small clinical studies reporting the
follow-up of CPVT patients taking beta-blockade. Leenhardt
et al. 60 reported two deaths among 21 French patients over 7
years, i.e. an incidence of sudden death of 1.36%/year. Priori
et al. 65 in a study of 30 European probands and 9 affected relatives
reported no deaths on beta-blockade after a mean follow-up of 46
months; 50% of patients had arrhythmia recurrence on drugs,
however, and 6 of 12 patients with ICDs had appropriate shocks
for ventricular arrhythmias; it is, of course, uncertain whether
these patients would have died without these shocks. In a study
of 21 Japanese patients,67 4 of 21 patients died over 6.8 year
follow-up, i.e. sudden death incidence of 2.8%/year, and a more
recent study of 12 European probands and 38 affected relatives
suggested a sudden death rate of 1%/year (1 of 50 patients died
over a 2-year follow-up).68 In the largest study of CPVT patients
reported to date,66 the incidence of fatal or near-fatal events in
those patients prescribed beta-blockade was 1.2% per year.
These ‘beta-blocker failures’ may be attributed in part but not
completely to non-compliance or lose dosage of medication.
Although the studies discussed above suggest ‘beta-blocker failures’ may be more common in CPVT than in LQTS, there are particular downsides to the use of the ICD in the CPVT population
that are very relevant to the decision whether or not to implant
1163
1164
C.J. Garratt et al.
Hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy is usually inherited as an autosomal
dominant trait with variable clinical penetrance and clinical
expression. In most patients, HCM is caused by mutations in
genes that encode cardiac sarcomeric proteins, but it is also associated with syndromes such as Noonan syndrome and inherited
metabolic disorders.72,73 Pathologically, HCM is characterized by
myocardial hypertrophy, typically affecting the interventricular
septum more than other myocardial segments, disorganization
(‘disarray’) of cardiac myocytes and myofibrils, myocardial fibrosis,
and small vessel disease.74 This myocardial disorganization is
thought to be the basis for ventricular arrhythmias and sudden
death associated with the syndrome.
Current ACC/AHA/ESC guidelines for
implantable cardioverter defibrillator
prescription in hypertrophic
cardiomyopathy
Class I. Implantable cardioverter defibrillator therapy should
be used for treatment in patients with HCM who have sustained
VT and/or VF (level of evidence: B).
Class IIa. Implantable cardioverter defibrillator implantation
can be effective for primary prophylaxis against SCD in patients
with HCM who have one or more major risk factor (Table 2) for
SCD (level of evidence: C).
Class IIb. EP testing may be considered for risk assessment for
SCD in patients with HCM (level of evidence: C).
Establishing a clinical diagnosis
Classical descriptions of the condition include symptoms of chest
pain (rest or with exercise), shortness of breath, or syncope on
exertion together with the presence of a systolic murmur. The
ECG is frequently abnormal in affected individuals and may
include criteria for left ventricular hypertrophy associated with
repolarization changes, isolated repolarization changes with
Table 2 Risk factors for sudden cardiac death in
hypertrophic cardiomyopathy
Major risk factors
Possible risk factors
Cardiac arrest (VF)
AF
Spontaneous sustained VT
Family history of SCD
Myocardial ischaemia
LV outflow obstruction
................................................................................
Unexplained syncope
High risk mutation
LV thickness ≥30 mm
Abnormal exercise BP
Competitive physical exercise
Non-sustained spontaneous VT
Risk of sudden death within specific
clinical and genetic subgroups
The reported annual incidence of SCD in patients with HCM has
declined from between 2 and 4% to 1% or less per year, a reflection,
perhaps, more of the identification of patients with milder disease
than the impact of modern treatment in high-risk patients.81
Sudden cardiac death occurs throughout life with a maximum incidence in adolescence and young adulthood, often without warning
signs or symptoms.82 Although there is an excess of deaths during
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The classes of ICD indications as defined by the ACC/AHA/ESC
Writing Committee can be summarized as follows and refer to
individuals who are receiving chronic optimal medical therapy
and otherwise have reasonable expectation of survival with a
good functional status for .1 year.
moderate-to-severe T wave inversion, and the presence of deep
Q waves. The current diagnosis of HCM rests, in the great majority
of cases, on the two-dimensional echocardiographic identification
of one or more segments of abnormally increased wall thickness
(.15 mm in adults) in a non-dilated left ventricle in the absence
of any other cardiac or systemic disease that could account for
hypertrophy.75 Borderline LV wall thicknesses of 13 or 14 mm in
an adult patient may constitute evidence of HCM, but in the
setting of systemic hypertension or sustained athletic activity the
diagnosis cannot be made on clinical grounds alone. Magnetic resonance imaging maybe useful in selected patients or family
members, particularly when echocardiographic studies are technically suboptimal or when segmental hypertrophy is confined to
unusual locations such as the anterolateral LV free wall or apex.76
Although LV hypertrophy may emerge in young children, the
onset of hypertrophy is typically in adolescence (13– 17 years)
and often complete by the time full growth and maturation are
achieved (18 to 21 years). LV outflow tract geometry is changed
with accelerated body growth during this time and systolic anterior
motion of the mitral valve causing dynamic obstruction to LV
outflow may develop. Delayed late-onset hypertrophy is currently
thought to be rare but is increasingly recognized; patients may
develop the first echocardiographic evidence of hypertrophy
during middle age.
It is evident from genetic studies that there is no true minimum
LV wall thickness diagnostic or pathognomonic for HCM and
indeed normal wall thickness is compatible with the presence of
an HCM-causing gene mutation. In the context of a family
history of HCM, otherwise unexplained mild electrocardiographic
or echocardiographic abnormalities will have a much higher probability of being an expression of a gene abnormality than in individuals without such a history. With this in mind, specific less
demanding criteria have been suggested for the diagnosis in adult
members of affected families, based on specific ‘major and
minor’ electrocardiographic and echocardiographic features.77
In recent years, mutations in the genes encoding contractile proteins have been identified as the cause of HCM. It is therefore likely
that that molecular genetic techniques and criteria will ultimately
become the tools for the classification of this disease. Currently,
however, the diagnostic yield (sensitivity) of genetic testing in clinical cases of clear familial HCM is in the region of 60%78; the yield is
dependent upon patient selection falling to significantly lower
levels if familial disease is not confirmed,79 i.e. a negative result is
common and does not exclude the diagnosis. The successful identification of a disease-causing mutation does, of course, allow rapid
and accurate screening of family members.80
HRUK position statement
or after strenuous exertion (see below), most occur during mild
exertion or sedentary activities.83 The mechanism underlying
most SCDs is thought to be ventricular tachyarrhythmia, but conduction disease and thrombo-embolism may account for some
cases. Rapid atrial fibrillation (AF) and myocardial ischaemia
appear to be important triggers for sudden ventricular arrhythmia.
Although sudden death rates in HCM populations are generally
low, the fact that sudden death frequently occurs without warning
in young and at most mildly symptomatic people provides a powerful stimulus to pre-emptively screen patients in order to identify
those at greatest risk. There are, however, several major challenges, not least the fact that the disease is relatively uncommon
making it difficult to collate large patient cohorts on which to
base robust risk algorithms. Heterogeneity in causation and clinical
phenotype also make group comparisons problematic and the substrate for sudden death may change during the long natural history
so that patients’ risk changes with time. The current approach to
risk stratification is based on an evaluation of a small number of
readily determined clinical parameters that have been considered
to be the most predictive of risk.1,75
Patients with one or more recognized major risk factors
for sudden cardiac death
The clinical features used to determine sudden death risk in HCM
are essentially surrogate markers of the severity of the underlying
myocardial disease, as direct functional assessment of the underlying disease process is currently not possible. In spite of the fact
that there is very little evidence that (with the exception of
prior cardiac arrest) any one risk factor is more predictive than
another, in the current AHA/ACC/ESC guidelines for the prevention of SCD, risk factors are sub-classified into ‘major’ and
‘possible’.1
Unexplained or recurrent syncope
Patients with HCM can experience syncope at rest and during all
grades of exertion. Many mechanisms are responsible including
left ventricular outflow tract obstruction, arrhythmia, and abnormal vascular reflexes. It is generally agreed that syncope should
always prompt a search for a mechanism and that should no treatable cause be identified, it should be considered a risk factor for
sudden death. Data on the association between syncope and
sudden death risk are few and contradictory, but in a recent
study, unprovoked syncope was associated with a relative risk of
2.27 for SCD.86
Family history of sudden cardiac death
Clinical and genetic studies have shown that some families with
HCM undoubtedly have a high risk of sudden death at a young
age.87 However, in a recent systematic review of the published literature,88 most published studies did not demonstrate a significant
relationship between a family history of SCD and cardiac death or
SCD. Only three studies demonstrated that family history of SCD
was an independent predictor of SCD, but it was relatively weak
with an average reported hazard ratio of only 1.27 (95% CI
1.16 –1.38). This apparently counterintuitive observation can be
explained by different definitions of a positive family history, variable clinical expression between individuals from the same family,
and the inherent difficulties in modelling family history as a risk
factor. For example, the cause of death in a relative is frequently
unknown and it is difficult to determine how the number of
sudden deaths in a family relates to the number of individuals at
risk. At present, therefore, the management of an individual with
an adverse family as their only risk factor is largely empiric and
often determined by psychological and social considerations.
Non-sustained ventricular tachycardia
In most studies, the prevalence of non-sustained ventricular tachycardia (NSVT) during ambulatory electrocardiography varies
between 20 and 30%.89,90 Its frequency increases with age and
the duration of electrocardiographic recording. The association
between NSVT and sudden death risk also varies between
studies, but the majority reports a relative risk in excess of 2.5.
There is very little evidence that the duration, frequency, or rate
of runs influences the prognostic significance of NSVT (defined
by a minimum rate of 120 bpm), but age does appear to be an
important modifier, with a relative risk of 4 in patients ,30
years of age.
Left ventricular hypertrophy
In two studies, the risk of sudden death in patients with a maximum
wall thickness .30 mm (or 25 mm in two or more segments) was
approximately four-fold.91,92 In a third study, age appeared to
modify the risk, with an annual sudden death rate of 17% in
patients with severe hypertrophy aged ,18 years compared
with 0% in older patients.93
Exercise blood pressure responses94 – 96
Upright exercise testing can be safely performed in the overwhelming majority of patients with HCM (including those with
left ventricular outflow tract obstruction). Several studies have
shown that a failure of blood pressure to rise appropriately, i.e.
by .20– 30 mmHg from baseline, is associated with an increased
cardiovascular mortality with a relative risk ranging from 2.4 to
9.6. In younger patients (age 40 –50 years or less), the presence
of an abnormal blood pressure response during exercise is
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Patients presenting with aborted cardiac arrest
or sustained VT
The easiest high-risk group to define are those (relatively rare)
patients who have already declared their propensity for fatal ventricular arrhythmia by surviving an episode of sustained ventricular
tachycardia or ventricular fibrillation (Table 2). Cumulative survival
(death or ICD discharge) in this group is 59% at 5 years.84,85 Sustained monomorphic ventricular tachycardia is rarely documented
prior to death, but is sometimes associated with apical left ventricular aneurysms. It is not known whether haemodynamically tolerated sustained ventricular tachycardia is associated with the same
adverse prognosis as syncopal ventricular arrhythmia. Multi-centre
registry data report yearly discharge rates of 10 –11% for secondary prevention in patients with a history of successfully resuscitated
ventricular tachycardia or ventricular fibrillation.85
Recommendation: Patients with HCM presenting with ventricular fibrillation/cardiac arrest or sustained VT without reversible
precipitant should undergo ICD implantation.
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1166
associated with a higher relative risk than in older patients. Several
mechanisms are responsible for the abnormal response, including
inappropriate vasodilatation in non-exercising muscles, splanchnic
venous pooling, poor augmentation of cardiac output, and possibly
sub-endocardial myocardial ischaemia due to microvascular
dysfunction.
When assessing blood pressure responses for the purpose of
determining risk, several caveats apply.
(i) It is normal for children and young adolescents to have a flat blood
pressure response during exercise.
(ii) Concomitant medication (beta-blockers, verapamil) may blunt the
blood pressure response.
(iii) Data on exercise blood pressure assume that maximum exercise
has been performed. Early cessation of exercise due to poor
effort or technical reasons needs to be considered when assessing
blood pressure response.
Atrial fibrillation98,99
Paroxysmal supraventricular arrhythmias occur during ambulatory
electrocardiographic monitoring in 30 –50% of patients.
Sustained AF is present in 5% of patients at diagnosis, and develops
in a further 10% in the subsequent 5 years. In a large study of 480
consecutive HCM patients, patients with AF had increased risk for
HCM-related death (OR 3.7) because of excess heart
failure-related mortality but not SCD. The risk associated with
AF was substantially greater in patients with outflow obstruction
or with earlier development of AF (,50 years of age).
High-risk mutation
As the large majority of patients with HCM have inherited disease,
all patients with HCM should be counselled on the implications of
the diagnosis for their families. Cascade screening, particularly
when guided by direct DNA testing, can identify asymptomatic
individuals at risk and can reassure relatives who are not at risk
of inheriting the disease. In patients with disease caused by
mutations in sarcomeric protein genes, some studies have
reported associations between particular mutations and a high
risk of SCD. Most notable are some families with cardiac troponin
T mutations that in spite of mild hypertrophy have a 50% mortality
before the age of 40 years. However, most of these studies are
limited by the small size of patient cohorts. Further, most
HCM-causing mutations are individually rare, making it difficult to
establish with confidence how a particular variant relates to risk
of SCD in an adequate number of patients. For these reasons,
the presence of a ‘high risk’ mutation is not currently regarded
as sufficient reason to implant an ICD in the absence of other clinical risk factors.
Intense physical exertion
As 40% of HCM sudden deaths occur following moderate-to-severe
exertion, current guidelines recommend that young patients with
HCM should not participate in competitive sports.100 However,
the increase in the relative risk of sudden death incurred by
regular participation in vigorous exercise is unknown, and it is
unclear how the inclusion of intense physical exercise as a possible
risk factor in the AHA/ACC/ESC guidelines impacts on the decision
to implant an ICD.
Recommendations for ICD implantation in patients with HCM
are based not on randomized trials but on observational data.
The approach to risk stratification recommended in the AHA/
ACC/ESC consensus guidelines is based on the concept of global
risk burden, whereby treatment decisions are determined by the
presence of a small number of risk factors. The presence of two
or more risk factors identifies a cohort of patients with an
annual sudden death risk of 3%, whereas the presence of any
single risk factor is associated with an annual risk of 1%.101
The ACC/AHA/ESC guidelines state that ICD implantation ‘can
be effective’ (a class IIa recommendation) in patients with one or
more of the recommended risk factors.
Single-risk factor patients: the ‘grey’ area
The advice to consider ICD for primary prevention in patients with
multiple risk factors appears straightforward and not controversial.
However, the inclusion of HCM patients with a single risk factor
could result in ICD implantation in 25% of patients.101 ICD implantation carries significant life-long morbidity and mortality risks that
may be particularly great in this young patient population; the risk
of harm may outweigh the benefit in a group with a ,1% per
annum risk of SCD or less. The AHA/ACC/ESC guidelines
reflect a concern that a recommendation to implant an ICD only
in patients with multiple risk factors would result in a failure to
treat individuals with solitary risk factors that may be sufficiently
concerning to warrant intervention (e.g. multiple sudden deaths
in a family or recurrent unexplained syncope). Although this
concern is understandable, it does mean that the recommendations for ICD implantation are loosely defined, reflecting large
differences in clinical practice, influenced as much by the biases
of individual clinicians and the perceived medico-legal consequences of inaction as by the clinical characteristics of individual
patients. Importantly, although we support the rationale of
stating that ICD implantation can be appropriate in the single-risk
factor patient, we do not support an interpretation that implantation should be the norm in this setting.
Recommendations: Patients with HCM and two or more recognized risk factors for SCD should be considered for ICD implantation. Patients with HCM and a single recognized risk factor for
SCD may, according to individual circumstances, be considered
for ICD implantation.
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Left ventricular outflow tract obstruction
Dynamic left ventricular outflow tract obstruction causes dyspnoea, chest pain, syncope and predisposes to the development
of atrial arrhythmias and stroke. At least three studies have
shown that outflow tract obstruction is associated with an
increased risk of sudden death.86,97 There is general agreement
that all patients with symptomatic outflow obstruction should
initially receive medical therapy (beta-blockers, verapamil, disopyramide). If symptoms persist, then patients should be considered for
invasive gradient reduction (surgery or alcohol septal ablation).
There are currently no data to support septal reduction for risk
management in asymptomatic (or medically controlled) outflow
tract obstruction.
C.J. Garratt et al.
1167
HRUK position statement
Arrhythmogenic right ventricular
cardiomyopathy
Arrhythmogenic right ventricular cardiomyopathy is a familial cardiomyopathy that may result in arrhythmia, heart failure, and
sudden death.104 – 107 It is characterized pathologically by progressive myocyte loss and fibrofatty replacement, with a predilection for
the right ventricle. Familial disease is common, with autosomal
dominant inheritance and incomplete penetrance; a recessive
form has also been described. The finding of disease-causing
mutations in genes encoding cell adhesion proteins (e.g. plakoglobin and desmoplakin) provides the basis for the hypothesis that
ARVC is a disease of the cell-to-cell junction. The inverse relation
between wall stress and wall thickness may explain the increased
susceptibility of the thin-walled right ventricle, and the predilection
of early disease for its thinnest portions, represented by the ‘triangle of dysplasia’ (diaphragmatic, infundibular, and apical right ventricular regions as well as in the left ventricle). These structural
changes disrupt the normal pattern of electrical activity across
the ventricular myocardium, leading to the potential for abnormal
electrical circuits and the generation of re-entrant ventricular
arrhythmias and ventricular fibrillation. The condition is, in
general, a progressive one and clinical features are rare below
the early teenage years.
The classes of ICD indications as defined by the ACC/AHA/ESC
Writing Committee can be summarized as follows and refer to
individuals who are receiving chronic optimal medical therapy
and otherwise have reasonable expectation of survival with a
good functional status for .1 year.
Class I. Implantable cardioverter defibrillator implantation is
recommended for the prevention of SCD in patients with
ARVC with documented sustained VT or VF (level of evidence:
B).
Class IIa. Implantable cardioverter defibrillator implantation
can be effective for the prevention of SCD in patients with
ARVC with extensive disease, including those with LV involvement, one or more affected family members with SCD, or
undiagnosed syncope when VT or VF has not been excluded
as the cause of syncope (level of evidence: C).
Class IIb. EP testing might be useful for the risk assessment of
SCD in patients with ARVC (level of evidence: C).
Establishing a clinical diagnosis
Classical features
Clinical presentation usually occurs during adolescence or in the
twenties with symptoms of palpitation, syncope, or sudden
death. The ECG at rest shows inverted T waves in the right precordial leads (V1–3) with or without incomplete right bundle
branch block. Occasionally distinct waves occur after the end of
the QRS complex, suggesting delayed activation of some portions
of the right ventricular wall (‘epsilon wave’). The ECG during
symptoms demonstrates the presence of sustained monomorphic
ventricular tachycardia with a left bundle branch block pattern or
bursts of ventricular ectopic activity. In late phases of the disease,
ARVC may be considered a differential diagnosis in patients presenting with heart failure, particularly if this has predominantly
right-sided features.
Pre-clinical or concealed phase
Although diagnosis is not difficult in those patients with typical features, patients with pre-clinical or mild disease pose much more of
a problem. Imaging (with echocardiography or magnetic resonance
imaging) during this phase may be negative because the disease
often involves only patchy and small areas of abnormal myocardium
in the ‘triangle of dysplasia’. A combination of multiple views and
imaging modalities are required for full assessment. A particular
problem is the interpretation of small right ventricular motion
abnormalities which may be responsible for false positive interpretation. Caution should be taken in the interpretation of RV apical
motion due to trabeculations and mid-apical lateral wall motion
due to the insertion of the moderator band. There is no ‘gold standard’ clinical or imaging test for the condition, and as a consequence
a scoring system based on the overall clinical picture has been
devised to assist in the diagnosis and standardize reporting of clinical
trials (1994 Task Force criteria108). Clinical features are subdivided
into major and minor. The diagnosis is fulfilled by the presence of
two major criteria, one major criterion plus two minor criteria or
four minor criteria from different groups. The majority of studies
reporting outcomes have used this diagnostic scoring system.
These have recently been updated and include more quantitative criteria, and abnormalities are defined on the basis of comparison with
normal subject data109 (Table 3). In the recently modified version, the
presence of inverted T waves in V1– 3 is considered a major
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Electrophysiological testing
The AHA/ACC/ESC guidelines suggest that electrophysiological
testing might have a role in some borderline cases (class IIb indication). Thirty six per cent of patients have inducible sustained ventricular tachycardia when using protocols consisting of three
premature stimuli delivered during three drive pacing cycle
lengths in the left and/or right ventricle.102 Ventricular tachycardia
induced by such aggressive protocols is associated with a higher
risk of cardiac events (defined as sudden death, cardiac arrest, or
syncope accompanied by ICD discharge), but the predictive accuracy for sudden death is very low. For these reasons, we would not
support the routine use of electrophysiology testing in this setting.
Conventional ventricular stimulation studies have been shown
to have low accuracy in predicting sudden death in HCM. There
is evidence however that a distinct electrophysiological abnormality, paced ventricular electrogram fractionation, may have greater
value for predicting SCD than conventional invasive criteria or
the non-invasive criteria discussed above.103 Ventricular electrogram fractionation is provoked using an invasive electrophysiological technique in which ventricular extrastimuli are introduced at
progressively shorter intervals at four separate sites in the right
ventricle. In a prospective study of 185 patients with an unequivocal diagnosis of HCM followed for 4.3 years, abnormal fractionation was shown to have greater positive predictive value for a
sudden death event than the use of single or combined conventional risk factors in patients with at least one risk factor.103 The
exact role of this technique in the selection of patients with
HCM for ICDs awaits further study in larger populations.
1168
Table 3 Comparison of original and revised Task Force criteria for diagnosis of arrhythmogenic right ventricular cardiomyopathy109
Original Task Force criteria
Revised Task Force criteria
.............................................................................................................................................................................................................................................
I. Global or regional dysfunction and structural alterationsa
Major
By 2D echo
Severe dilatation and reduction of RV ejection fraction with no (or only
mild) LV impairment
Regional RV akinesia, dyskinesia, or aneurysm
Localized RV aneurysms (akinetic or dyskinetic areas with diastolic
bulging)
and one of the following (end diastole):
Severe segmental dilatation of the RV
PLAX RVOT ≥32 mm [corrected for body size (PLAX/BSA) ≥19 mm/m2]
PSAX RVOT ≥36 mm [corrected for body size (PSAX/BSA) ≥21 mm/m2]
or fractional area change ≤33%
By MRI
Regional RV akinesia or dyskinesia or dyssynchronous RV contraction
and 1 of the following:
Ratio of RV end-diastolic volume to BSA ≥110 mL/m —2 (male) or ≥100 mL/m2 (female)
—or RV ejection fraction ≤40%
By RV angiography Regional RV akinesia, dyskinesia, or aneurysm
Minor
Mild global RV dilatation and/or ejection fraction reduction with
normal LV
Mild segmental dilatation of the RV
Regional RV hypokinesia
By 2D echo
Regional RV akinesia or dyskinesia
and one of the following (end diastole):
PLAX RVOT ≥29 to
, 32 mm [corrected for body size (PLAX/BSA) ≥16 to ,19 mm/m2]
PSAX RVOT ≥32 to , 36 mm [corrected for body size (PSAX/BSA) ≥18 to ,21 mm/m2]
or fractional area change .33% to ≤40%
By MRI
Regional RV akinesia or dyskinesia or dyssynchronous RV contraction
and one of the following:
Ratio of RV end-diastolic volume to BSA ≥100 to
, 110 mL/m2 (male)
or ≥90 to ,100 mL/m (female)
2
or RV ejection fraction .40% to ≤45%
II. Tissue characterization of wall
Major
Residual myocytes ,60% by morphometric analysis (or ,50% if estimated), with fibrous replacement of the RV free wall
myocardium in one or more sample, with or without fatty replacement of tissue on endomyocardial biopsy
C.J. Garratt et al.
Continued
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Fibrofatty replacement of myocardium on endomyocardial biopsy
Residual myocytes 60– 75% by morphometric analysis (or 50– 65% if estimated), with fibrous replacement of the RV free wall
myocardium in one or more sample, with or without fatty replacement of tissue on endomyocardial biopsy
III. Repolarization abnormalities
Major
Inverted T waves in right precordial leads (V1, V2, and V3) or beyond in individuals .14 years of age (in the absence of complete right
bundle-branch block QRS ≥120 ms)
Minor
Inverted T waves in right precordial leads (V2 and V3) (people age .12
years, in the absence of right bundle-branch block)
HRUK position statement
Minor
Inverted T waves in leads V1 and V2 in individuals .14 years of age (in the absence of complete right bundle-branch block) or in V4, V5,
or V6
Inverted T waves in leads V1, V2, V3, and V4 in individuals .14 years of age in the presence of complete right bundle-branch block
IV. Depolarization/conduction abnormalities
Major
Epsilon waves or localized prolongation (.110 ms) of the QRS complex
in right precordial leads (V1 to V3)
Minor
Epsilon wave (reproducible low-amplitude signals between end of QRS complex to onset of the T wave) in the right precordial leads
(V1 to V3)
Late potentials (SAECG)
Late potentials by SAECG in one or more of three parameters in the absence of a QRS duration of ≥110 ms on the standard ECG
Filtered QRS duration (fQRS) ≥114 ms
Duration of terminal QRS ,40 mV (low-amplitude signal duration) ≥38 ms
Root-mean-square voltage of terminal 40 ms ≤20 mV
Terminal activation duration of QRS ≥55 ms measured from the nadir of the S wave to the end of the QRS, including R′ , in V1, V2, or
V3, in the absence of complete right bundle-branch block
V. Arrhythmias
Major
Non-sustained or sustained ventricular tachycardia of left bundle-branch morphology with superior axis (negative or indeterminate
QRS in leads II, III, and aVF and positive in lead aVL)
Minor
Left bundle-branch block-type ventricular tachycardia (sustained and
non-sustained) (ECG, Holter, exercise)
Non-sustained or sustained ventricular tachycardia of RV outflow configuration, left bundle-branch block morphology with inferior
axis (positive QRS in leads II, III, and aVF and negative in lead aVL) or of unknown axis
Frequent ventricular extra-systoles (.1000 per 24 h) (Holter)
.500 ventricular extrasystoles per 24 h (Holter)
VI. Family history
Major
ARVC/D confirmed in a first-degree relative who meets current Task Force criteria
ARVC/D confirmed pathologically at autopsy or surgery in a first-degree relative
Identification of a pathogenic mutationb categorized as associated or probably associated with ARVC/D in the patient
under evaluation
Continued
1169
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Familial disease confirmed at necropsy or surgery
1170
PLAX, parasternal long-axis view; RVOT, RV outflow tract; BSA, body surface area; PSAX, parasternal short-axis view; aVF, augmented voltage unipolar left foot lead; aVL, augmented voltage unipolar left arm lead.
Diagnostic terminology for original criteria: This diagnosis is fulfilled by the presence of two major, or one major plus two minor criteria or four minor criteria from different groups. Diagnostic terminology for revised criteria: definite diagnosis:
two major or one major and two minor criteria or four minor from different categories; borderline: one major and one minor or three minor criteria from different categories; possible: one major or two minor criteria from different categories.
a
Hypokinesis is not included in this or subsequent definitions of RV regional wall motion abnormalities for the proposed modified criteria.
b
A pathogenic mutation is a DNA alteration associated with ARVC/D that alters or is expected to alter the encoded protein, is unobserved, or rare in a large non-ARVC/D control population, and either alters or is predicted to alter the
structure or function of the protein or has demonstrated linkage to the disease phenotype in a conclusive pedigree.
Table reproduced with permission from Marcus et al. 109
Premature sudden death (,35 years of age) due to suspected ARVC/D in a first-degree relative
Familial history (clinical diagnosis based on present criteria)
ARVC/D confirmed pathologically or by current Task Force criteria in a second-degree relative
History of ARVC/D in a first-degree relative in whom it is not possible or practical to determine whether the family member meets
current Task Force criteria
Family history of premature sudden death (,35 years of age) due to
suspected ARVC/D
Minor
Revised Task Force criteria
Original Task Force criteria
Table 3 Continued
diagnostic criterion, as is the documentation of NSVT of LBBB morphology with superior axis. The confirmation of disease in a firstdegree relative either by clinical (Task Force) criteria or by the identification of a pathogenic mutation is also considered a major criterion,
reflecting the greatly increased probability of disease under these circumstances (Table 3).
Genetic testing
Most cases of ARVC are thought to be caused by autosomal dominantly inherited mutations in genes encoding different proteins of
the desmosome of cardiomyocytes. The diagnostic yield (or sensitivity; a positive result in established cases) for the commonest (the
PKP2 gene) is 30% or less, so the value of genetic testing in a purely
diagnostic role is limited.
Risk of sudden death within specific
clinical and genetic subgroups
Patients presenting with ventricular arrhythmias
The risk of sudden death associated with ARVC patients presenting with ventricular arrhythmias has been addressed by the study of
Corrado et al. 110 They reported a multicentre observational study
of the outcomes of 132 ARVC patients who had undergone ICD
implantation because of a history of cardiac arrest (10% of total
implants), sustained ventricular tachycardia (62% of implants), or
syncope without electrocardiographic documentation (16%). All
patients had an ‘unequivocal’ diagnosis of ARVC, fulfilling either
two major or one major plus two minor diagnostic criteria recommended by the 1994 Task Force of the European Society of
Cardiology. No patient with only minor criteria entered the
study. Analysis of projected survival was based on appropriate defibrillator shocks for sustained ventricular fibrillation or flutter
recorded on stored electrograms, rather than shocks triggered
by ventricular tachycardia that may not have been life-threatening.
Patients who had ICDs implanted because of presentation with
cardiac arrest had a risk of subsequent sudden death or ‘life-saving’
shock of 21%/year. The corresponding appropriate shock rates for
the other clinical groups were as follows: poorly tolerated VT 9%/
year, syncope without ECG documentation 8%/year, and welltolerated VT of 1%/year. Multivariate analysis revealed that, in
addition to presentation with cardiac arrest or poorly tolerated
VT, left ventricular involvement was an independent predictor of
potentially lethal ventricular arrhythmias.
The largest series of US patients with ARVC was described by
Dalal et al. 111 from the Johns Hopkins ARVC registry. The authors
reported the details of ICD therapy in the Johns Hopkins registry
in a separate report.112 Forty-four of the 67 patients with ICDs
received appropriate device therapies during a mean follow-up of
4.4 years. An appropriate shock does not, of course, equate to a
life saved; the authors described life-saving therapy as that delivered
in response to a ventricular arrhythmia with a rate greater than
240 bpm; on these criteria, 14 patients fulfilled these criteria, i.e.
an overall incidence of ‘life-saving’ shock of 5%/year.
Recommendation: Arrhythmogenic right ventricular cardiomyopathic patients presenting with ventricular fibrillation/cardiac arrest
or poorly tolerated VT should undergo ICD implantation. Arrhythmogenic right ventricular cardiomyopathic patients presenting with
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.............................................................................................................................................................................................................................................
C.J. Garratt et al.
HRUK position statement
syncope (when VT/VF has not been excluded as the cause of
syncope) should undergo ICD implantation.
Additional insight into predictors of sudden death is provided by
the study of Hulot et al.,113 who described outcomes of 130
patients who fulfilled Task Force criteria. In this study, most
(78%) had suffered at least one episode of ventricular tachycardia
and over half had evidence of gross RV dilation and dysfunction.
After a mean follow-up of 8 years, there were 7 SCDs and 14
deaths as a result of progressive heart failure. All patients who
died of a cardiovascular cause had at least one episode of left
bundle branch block VT. Multivariate analysis showed that after
the adjustment for history of syncope, ventricular tachycardia,
and QRS dispersion, clinical signs of right ventricular failure and
left ventricular dysfunction both remained independently associated with cardiovascular mortality.
Recommendation: Arrhythmogenic right ventricular cardiomyopathic patients presenting with ventricular arrhythmias and severe
structural disease should be considered for ICD implantation.
Electrophysiological testing
The electrophysiological study is of limited value in identifying
patients at risk of lethal ventricular arrhythmias. Programmed ventricular stimulation has a low predictive accuracy,110 with 50% of
both false positive and false negative results. This finding is in
keeping with the limited predictive value of electrophysiological
study in conditions other than ischaemic heart disease, such as
hypertrophic and dilated cardiomyopathy. Electrophysiological
testing was of limited practical value in predicting appropriate
shocks.112 All of the patients with a history of spontaneous sustained VT had inducible arrhythmias at electrophysiology study,
but among those patients with other presentations inducible VT
did not predict subsequent ICD shocks.
Complications of implantable
cardioverter defibrillators in
familial sudden death syndromes
Although the ICD can, without doubt, be a life-prolonging therapy
in the familial SCD syndromes, there are significant negatives in
terms of both morbidity and, occasionally, mortality associated
with these devices.
Two relatively large series in adult patients with LQTS have been
reported: the first from the US20 was considered by some to have
exaggerated the likely benefit of ICD therapy,21 with the second
from Germany possibly having more relevance to practice in the
UK.115 In this second group of 27 patients implanted between
1994 and 2003, 37% of the patients had 178 ‘appropriate’ shocks,
although the authors acknowledge these episodes may have represented potentially self-terminating torsade de pointes in many
cases. Twenty per cent of the patients had electrical storms, and
there was also a 30% incidence of ‘inappropriate’ shocks in these
relatively young patients. Patients with Brugada syndrome suffer a
similarly high rate of device complications. The ongoing risk of complications (8.9% per annum) and the high frequency of inappropriate
shocks (2.5 times higher than appropriate) in an asymptomatic and
young age group are of concern.116
Implantation of ICDs is not without the risk of death as well as
morbidity. In a study of 132 patients with ARVC,110 five patients
required an additional pacing lead during the follow-up period of
39 months because of undersensing or pacing failure, and one
patient died from endocarditis secondary to device infection.
Several other published series have confirmed the relatively high
incidence of device-related complications in ARVC patients.
Wichter and et al. 117 described a 37% lead-related complication
rate at 7 years post-implant. More recently, Lin et al. 118 have
described similarly high rates of device complications and inappropriate shocks in patients with HCM. These findings (in particular the risk of death associated with device implantation) reinforce
the need to weigh carefully the relative risks and benefits of ICD
implantation in specific patients rather than take an approach of
recommending an ICD whenever a possible risk of sudden death
associated with a familial syndrome has been identified.
Special considerations concerning
implantable cardioverter
defibrillators in children
The recommendations in this document refer to the adult population. Clinical decision-making with regard to the use of ICDs in children with familial SCD syndromes is particularly challenging. Clinical
diagnosis can be much more difficult in this patient group and the
phenotype is very likely to change with periods of rapid growth. Evidence regarding the assessment of risk of sudden death in children is
significantly more limited than that available for the adult population.
Implantable cardioverter defibrillator implantation in children is
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Asymptomatic patients with mild disease
The largest systematic study of ARVC in family members of sudden
death victims over a long period is that of Nava et al.,114 who
described the outcome of 151 affected individuals from 37 families
with a mean follow-up of 8.5 years. The 37 probands presented
with either autopsy findings (19 individuals) or ventricular arrhythmias. Patients had to fulfil 1994 Task Force criteria to be considered affected. Most had mild echocardiographic abnormalities
(64% mild, 30% moderate, and 6% severe) and all were advised
to avoid physical exercise and sports activity, but only two patients
underwent ICD implantation. During a mean follow-up period of
8.5 years, only one family member died suddenly (mortality rate
of 0.08%/year). The authors suggested that the apparent contrast
between a malignant family history and the relatively benign
follow-up in their series could be explained by early diagnosis,
exercise restriction, and anti-arrhythmic therapy. The most
commonly used drugs were beta-blockade and amiodarone.
By comparing available clinical data in probands who died suddenly
and in affected living patients, only a history of syncope was predictive of sudden death. Thus, the risk of an ICD (particularly in thinwalled right ventricles) must be weighed against the small risk of
sudden death in these patients.
Recommendation: Arrhythmogenic right ventricular cardiomyopathic patients who are asymptomatic with mild disease are at low
risk of sudden death, and the risks of ICD therapy may outweigh
the benefits in this group.
1171
1172
Patients attitudes towards
implantable cardioverter
defibrillator therapy
In this paper, we have focused on the physician/device implanters’
views of the relative balance between risks of sudden death and
those of device implantation in patients with familial sudden death syndromes, although with an attempt to place themselves in the position
of a patient. The key role of the physician in the decision-making
process is to provide the patient (or their parents) with a recommendation, together with a discussion of the reasons behind that recommendation and possible alternative options. This discussion
should, of course, be targeted on the particular circumstances of
that patient and it is important that the patient’s views and attitudes
towards their disease and ICDs are taken into account. For instance,
the physician may have identified clear evidence of mild disease in a
sibling of a sudden death victim shown at post-mortem to have
ARVC. The physician may have explained that long-term follow-up
studies have indicated a good prognosis in this situation, with an estimated risk of sudden death of ,1% per year and that the risks of an
ICD might well outweigh the benefits in this situation. However, the
long-term anxiety associated with the unheralded death of a sibling
from the same disease may be such that an ICD confers considerable
psychological benefit over and above any survival benefit; under these
circumstances implantation of an ICD may be the best course of action.
Summary and conclusions
Although the decision regarding defibrillator implantation in a
patient with a familial syndrome is likely to be one of the most significant for any particular individual, the clinical decision-making
process itself is complex and requires interpretation and extrapolation of information from a number of different sources. Although
the specific conditions described in this document differ in terms
of clinical features and prognosis, it is possible and logical to take
an approach to determining a threshold for ICD implantation
that is common to all of the familial SCD syndromes.
Conflict of interest: A.J.C. is an advisor/speaker for Medtronic
and Boston Scientific, a speaker for Biotronik, and has received
research funds from St Jude.
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