HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013

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HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis
and Management of Patients with Inherited Primary
Arrhythmia Syndromes
Silvia G. Priori, MD, PhD, (HRS Chairperson)
1
, Arthur A. Wilde, MD, PhD, (EHRA Chairperson)
2
,
Minoru Horie, MD, PhD, (APHRS Chairperson)
3
, Yongkeun Cho, MD, PhD, (APHRS Chairperson)
4
,
Elijah R. Behr, MA, MBBS, MD, FRCP
5
, Charles Berul, MD, FHRS, CCDS
6
,NicoBlom,MD,PhD
7,*
,
Josep Brugada, MD, PhD
8
, Chern-En Chiang, MD, PhD
9
, Heikki Huikuri, MD
10
, Prince Kannankeril, MD
11,‡
,
Andrew Krahn, MD, FHRS
12
, Antoine Leenhardt, MD
13
,ArthurMoss,MD
14
, Peter J. Schwartz, MD
15
,
Wataru Shimizu, MD, PhD
16
, Gordon Tomaselli, MD, FHRS
17,†
, Cynthia Tracy, MD
18,%
From the
1
Maugeri Foundation IRCCS, Pavia, Italy, Department of Molecular Medicine, University of Pavia, Pavia, Italy and
New York University, New York, New York,
2
Department of Cardiology, Academic Medical Centre, Amsterdam, Netherlands,
Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia,
3
Shiga University of Medical Sciences, Otsu, Japan,
4
Kyungpook National University Hospital, Daegu, South Korea,
5
St.
Georges University of London, United Kingdom,
6
Children’s National Medical Center, Washington, DC, United States,
7
Academical Medical Center, Amsterdam, Leiden University Medical Center, Leiden, Netherlands,
8
University of Barcelona,
Barcelona, Spain,
9
Taipei Veteran’s General Hospital, Taipei, Taiwan,
10
Oulu University Central Hospital, Oulu, Finland,
11
Vanderbilt Children’s Hospital, Nashville, Tennessee, United States,
12
Sauder Family and Heart and Stroke Foundation
University of British Columbia, British Columbia, Canada,
13
Bichat University Hospital, Paris, France,
14
University of
Rochester Medical Center, Rochester, New York, United States,
15
Department of Molecular Medicine, University of Pavia,
Pavia, Italy,
16
Nippon Medical School, Tokyo, Japan,
17
Johns Hopkins University, Baltimore, Maryland, United States, and
18
George Washington University Medical Center, Washington, DC, United States.
Document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in
June 2013
TABLE OF CONTENTS
1 Introduction ............................................... xxx
2 Long QT Syndrome (LQTS)...................... xxx
3 Brugada Syndrome (BrS) ........................... xxx
4 Catecholaminergic Polymorphic Ventri-
cular Tachycardia (CPVT) ......................... xxx
5 Short QT Syndrome (SQTS)...................... xxx
6 Early Repolarization (ER) ......................... xxx
7 Progressive Cardiac Conduction Disease
(PCCD) ...................................................... xxx
8 Unexplained Cardiac Arrest: Idiopathic VF xxx
9 Unexplained Cardiac Arrest: Sudden
Unexplained Death Syndrome (SUDS)
and Sudden Unexplained Death in
Infancy (SUDI) .......................................... xxx
10 Inherited Arrhythmia Clinics ..................... xxx
1. Introduction
This international consensus statement is the collaborative
effort of three medical societies representing electrophysiology
in North America, Europe and Asian-Pacific area: the Heart
Rhythm Society (HRS), the European Heart Rhythm Associ-
ation (EHRA) and the Asia Pacific Heart Rhythm Society. The
objective of the consensus document is to provide clinical
guidance for diagnosis, risk stratification and management of
patients affected by inherited primary arrhythmia syndromes. It
summarizes the opinion of the international writing group
members based on their own experience and on a general
review of the literature with respect to the clinical data on
patients affected by channelopathies.
%
Representative for American College of Cardiology;
†
Representative for
American Heart Association;
‡
Representative for Pediatric and Congenital
Electrophysiology Society;
*
Representative for Association for European
Pediatric and Congenital Cardiology
Developed in partnership with the Heart Rhythm Society (HRS), the
European Heart Rhythm Association (EHRA), a registered branch of the
European Society of Cardiology, and the Asia Pacific Heart Rhythm Society
(APHRS); and in collaboration with the American College of Cardiology
Foundation (ACCF), the American Heart Association (AHA), the Pediatric
and Congenital Electrophysiology Society (PACES) and the Association
for European Pediatric and Congenital Cardiology (AEPC). Address
correspondence: Sheila Tynes. E-mail address: STynes@hrsonline.org.
1547-5271/$-see front matter BHeart Rhythm Society, European Heart Rhythm Association,
a registered branch of the European Society of Cardiology, and the Asia Pacific Heart Rhythm Society http://dx.doi.org/10.1016/j.hrthm.2013.05.014

This document does not address the indications of genetic
testing in patients affected by inherited arrhythmias and their
family members. Diagnostic, prognostic, and therapeutic
implications of the results of genetic testing also are not
included in this document because this topic has been
covered by a recent publication
1
coauthored by some of
the contributors of this consensus document, and it remains
the reference text on this topic. Guidance for the evaluation
of patients with idiopathic ventricular fibrillation, sudden
arrhythmic death syndrome and sudden unexplained death in
infancy, which includes genetic testing, are provided as these
topics were not covered in the previous consensus statement.
Developing guidance for genetic diseases requires adap-
tation of the methodology adopted to prepare guidelines for
clinical practice. Documents produced by other medical
societies have acknowledged the need to define the criteria
used to rank the strength of recommendation for genetic
diseases.
2
The most obvious difference encountered for inherited
diseases is that randomized and/or blinded studies do not exist
in this field. Therefore most of the available data derive from
registries that have followed patients and recorded outcome
information. As a consequence, all consensus recommendations
are level of evidence (LOE) C (i.e., based on experts’opinions).
The consensus recommendations in this document use the
commonly used Class I, IIa, IIb and III classification and the
corresponding language: “is recommended”for Class I con-
sensus recommendation; “can be useful”for a Class IIa
consensus recommendation; “may be considered”to signify
a Class IIb consensus recommendation; and “should not”or “is
not recommended”for a Class III consensus recommendation
(failure to provide any additional benefit and may be harmful).
Definitions of special terms used in the document
In the consensus document, the following terms will be
defined as:
Syncope: In the context of inherited arrhythmogenic
disorders, the occurrence of “syncope”is an important
indicator of arrhythmic risk. Although there is no
definition to differentiate a syncopal episode caused by
ventricular arrhythmias from an otherwise unexplained
syncope, in the context of this document, the term
“syncope”implies the exclusion of events that are likely
due to vasovagal events such as those occurring during
abrupt postural changes, exposure to heat and dehydra-
tion, emotional reactions to events such as blood drawing,
etc. We refer to the guidelines of ESC and AHA/ACCF
for the differential diagnoses of syncope.
3,4
Symptomatic individuals: The term “symptomatic”
refers to individuals who have experienced ventricular
arrhythmias (usually ventricular tachycardia or resusci-
tated ventricular fibrillation), or syncopal episodes (see
definition above). The presence of symptoms is, in some
of the channelopathies, an independent predictor of
cardiac arrest at follow-up.
Arrhythmic events: The term refers to the occurrence of
symptomatic or asymptomatic sustained or nonsustained
spontaneous ventricular tachycardia, or unexplained syn-
cope/resuscitated cardiac arrest.
Concealed mutation-positive patients: This term is
used to refer to individuals without clinical symptoms
or phenotype of a channelopathy who carry the gene-
tic defect present in clinically affected members of the
family.
Methodological aspects and instructions
for the consultation of the document
When considering the guidance from this document, it is
important to remember that there are no absolutes governing
many clinical situations. The final judgment regarding care of
a particular patient must be made by the health care provider
and the patient in light of all relevant circumstances. Recom-
mendations are based on consensus of the writing group
following the Heart Rhythm Society’s established consensus
process. It is recognized that consensus does not mean
unanimous agreement among all writing group members.
We identified the aspects of patients'care for which a true
consensus could be found. Surveys of the entire writing group
were used. The authors received an agreement that was equal
to or greater than 84% on all recommendations; most
recommendations received agreement of 94% or higher.
This statement is directed to all health care professionals
who are involved in the management of (1) individuals who
survived a cardiac arrest at a young age (usually defined as
o40 years) in the absence of a clinical diagnosis of cardiac
disease, despite extensive clinical assessment; (2) family
members of individuals who died suddenly at young age
with a negative autopsy; (3) in patients and family members
in whom the diagnosis of a channelopathy is clinically
possible, likely, or established; and (4) young patients with
unexplained syncope.
All members of this document writing group provided
disclosure statements of all relationships that might present
real or perceived conflicts of interest. Disclosures for all
members of the writing group are published in Appendix A.
2. Long QT Syndrome (LQTS)
Expert Consensus Recommendations on LQTS Diagnosis
1. LQTS is diagnosed:
a. In the presence of an LQTS risk score ≥3.5 in the
absence of a secondary cause for QT prolongation
and/or
b. In the presence of an unequivocally pathogenic
mutation in one of the LQTS genes or
c. In the presence of a QT interval corrected for heart rate
using Bazett'sformula(QTc)≥500 ms in repeated 12-
lead electrocardiogram (ECG) and in the absence of a
secondary cause for QT prolongation.
2. LQTS can be diagnosed in the presence of a QTc between
480–499 ms in repeated 12-lead ECGs in a patient with
Heart Rhythm, Vol 0, No 0, Month 20132

unexplained syncope in the absence of a secondary cause
for QT prolongation and in the absence of a pathogenic
mutation.
Expert Consensus Recommendations on LQTS Therapeutic
Interventions
Class I 1. The following lifestyle changes are recom-
mended in all patients with a diagnosis of
LQTS:
a) Avoidance of QT-prolonging drugs (www.
qtdrugs.org)
b) Identification and correction of electrolyte
abnormalities that may occur during
diarrhea, vomiting, metabolic conditions or
imbalanced diets for weight loss.
2. Beta-blockers are recommended for patients
with a diagnosis of LQTS who are:
a) Asymptomatic with QTc ≥470 ms and/or
b) Symptomatic for syncope or documented
ventricular tachycardia/ventricular
fibrillation (VT/VF).
3. Left cardiac sympathetic denervation (LCSD) is
recommended for high-risk patients with a
diagnosis of LQTS in whom:
a) Implantable cardioverter defibrillator (ICD)
therapy is contraindicated or refused and/or
b) Beta-blockers are either not effective in
preventing syncope/arrhythmias, not
tolerated, not accepted or contraindicated.
4. ICD implantation is recommended for patients
with a diagnosis of LQTS who are survivors of
a cardiac arrest.
5. All LQTS patients who wish to engage in
competitive sports should be referred to a
clinical expert for evaluation of risk.
Class IIa 6. Beta-blockers can be useful in patients with a
diagnosis of LQTS who are asymptomatic with
QTc ≤470 ms.
7. ICD implantation can be useful in patients
with a diagnosis of LQTS who experience
recurrent syncopal events while on beta-
blocker therapy.
8. LCSD can be useful in patients with a diagnosis
of LQTS who experience breakthrough events
while on therapy with beta-blockers/ICD.
9. Sodium channel blockers can be useful,as
add-on therapy, for LQT3 patients with a QTc
4500 ms who shorten their QTc by 440 ms
following an acute oral drug test with one of
these compounds.
Class III 10. Except under special circumstances, ICD
implantation is not indicated in asymp-
tomatic LQTS patients who have not been
tried on beta-blocker therapy.
Epidemiology
Patients affected by the long QT syndrome (LQTS) have
been identified all over the world and in all ethnic groups.
A possible exception is represented by a paucity of cases
identified among black Africans and among African-
Americans. Among Caucasians, the prevalence of LQTS
has been established by a prospective ECG study, comple-
mented by molecular screening, performed on over 44,000
infants at age 15–25 days.
5
LQTS disease-causing mutations
were identified in 43% and 29% of the infants with a QTc
exceeding 470 and 460 milliseconds (ms), respectively.
These findings demonstrate a prevalence of about 1:2000
apparently healthy live births (95% CI, 1:1583 to 1:4350).
This prevalence reflects only infants with an abnormally long
QTc and does not take into account the significant number of
“concealed mutation-positive patients.”
Genetic variants
Since 1995, when the first three genes responsible for LQTS
were identified,
6–8
molecular genetic studies have revealed a
total of 13 genetic forms of congenital LQTS caused by
mutations in genes encoding potassium-channel proteins,
sodium-channel proteins, calcium channel-related factors,
and membrane adaptor proteins. Patients with LQT1,LQT2,
and LQT3 genotypes with mutations involving KCNQ1,
KCNH2, and SCN5A make up over 92% of patients with
genetically confirmed LQTS. Up to 15%–20% of patients
with LQTS remain genetically elusive.
1
Mutations in auxil-
iary β-subunits to KCNQ1 (KCNE1, LQT5) and KCNH2
(KCNE2, LQT6) are infrequent, but they result in clinical
phenotypes similar to patients with mutations in their
associated α-subunits of KCNQ1 and KCNH2. A recessive
form of LQTS, the Jervell and Lange-Nielsen syndrome,
involves the same (homozygous) or different (compound
heterozygous) KCNQ1 mutations from both parents, is more
virulent and is associated with deafness. Mutations in KCNJ2
(Kir2.1, LQT7) result in the neurologic musculoskeletal
Andersen-Tawil syndrome with associated QT prolongation.
The remaining LQTS genotypes (LQT4 and LQT8-13) have
each been identified in just a few families or in single
individuals.
Common variants in the LQTS genes (single nucleotide
polymorphisms [SNPs]), and in some cases unrelated genes,
are thought to contribute to the variable penetrance of LQTS
within affected family members having the same gene
mutation.
9
Clinical manifestations
The clinical manifestations of LQTS fall under two main
categories: the arrhythmic events and the electrocardio-
graphic (ECG) aspects.
The arrhythmic events are due to runs of torsades de
pointes VT, which, according to its duration, produces
syncope, cardiac arrest, and—when it deteriorates into VF
—sudden death. Among untreated patients, the natural
history is represented by the occurrence of a number of
3Priori et al Expert Consensus Statement on Inherited Primary Arrhythmia Syndromes

syncopal episodes, eventually leading to sudden death.
Sudden death as a first manifestation represents the main
rationale for the treatment of asymptomatic patients. Atrial
arrhythmias, specifically atrial fibrillation, are more frequent
in LQTS patients compared to controls.
10,11
The conditions associated with arrhythmic events are, to a
large extent, gene-specific,
12
with most arrhythmic events
occurring during physical or emotional stress in LQT1, at rest
or in association with sudden noises in LQT2 patients, and at
rest or during sleep in LQT3 patients.
The ECG alterations are important and numerous. While
the prolongation of the QT interval is the hallmark of LQTS,
it is not always present. Indeed, between 10% (LQT3) and
37% (LQT1) of genotype-positive patients have a QT
interval within normal limits at rest.
13
Ventricular repolari-
zation is not only prolonged but often presents bizarre
morphologic alterations, some of which tend to be gene-
specific.
14
Macroscopic T-wave alternans
15
is perhaps the
most distinctive ECG pattern of LQTS, and is a marker of
high cardiac electrical instability. Notches on the T-wave are
rather typical for LQT2 and their presence is associated with
a higher risk for arrhythmic events.
16
Long sinus pauses are
not infrequent among LQT3 patients.
Diagnosis
The diagnosis of LQTS is mainly based on measurement of
the QT interval corrected for heart rate (QTc) using Bazett's
formula. When using a prolonged QTc to diagnose LQTS,
one must exclude secondary causes of QTc prolongation that
can occur with drugs, acquired cardiac conditions, electro-
lyte imbalance, and unbalanced diets. A scoring system has
been established, which takes into account the age of the
patient, medical and family history, symptoms, and QTc and
provides a probability of the diagnosis of LQTS.
17,18
Approximately 20%–25% of patients with LQTS con-
firmed by the presence of an LQTS gene mutation may have a
normal range QTc.
13,19
The use of provocative tests for QT
measurement during change from a supine to standing
position,
20
in the recovery phase of exercise testing,
21,22
or
during infusion of epinephrine
23,24
has been proposed to
unmask LQTS patients with normal QTc at resting ECG.
These tests may be considered in uncertain cases. However,
the clinical use of this test requires more extensive validation.
Risk stratification
Individuals at the extremes of the curve, those at very high or
at very low risk, are easy to identify. For the larger group, in
the gray area, risk stratification is difficult and can be fraught
with errors in either direction. There are genetic and clinical
clues that facilitate risk assessment.
Specific genetic variants, such as the Jervell and Lange-
Nielsen syndrome
25
and the extremely rare Timothy syn-
drome (LQT8)
26
are highly malignant, manifest with major
arrhythmic events very early, and respond poorly to thera-
pies. Within the most common genetic groups, specific
locations, types of mutations, and degree of mutation
dysfunction are associated with different risks. Mutations
in the cytoplasmic loops of LQT1,
27,28
LQT1 mutations with
dominant-negative ion current effects,
29
and mutations in the
pore region of LQT2
29,30
are associated with higher risk, and
the same is true even for some specific mutations with an
apparently mild electrophysiological effect.
31
By contrast,
mutations in the C-terminal region tend to be associated with
a mild phenotype.
32
Clinically, there are several patterns and groups associ-
ated with differential risk. High risk is present whenever QTc
4500 ms
13,33
and becomes extremely high whenever QTc
4600 ms. Patients with a diagnosis of LQTS who are
identified by genetic testing as having two unequivocally
pathogenic variants and a QTc 4500 ms (including homo-
zygous mutations as seen in patients with Jervell and Lange-
Nielsen syndrome) are also at high risk, in particular when
they are symptomatic. The presence of overt T-wave
alternans, especially when evident despite proper therapy,
is a direct sign of electrical instability and calls for preventive
measures. Patients with syncope or cardiac arrest before age
7 have a higher probability of recurrence of arrhythmic
events while on beta-blockers.
34
Patients who have syncope
or cardiac arrest in the first year of life are at high risk for
lethal events and may not be fully protected by the traditional
therapies.
35,36
Patients who suffer arrhythmic events despite
being on full medical therapy are at higher risk.
By contrast, it also is possible to identify patients at lower
risk. Concealed mutation-positive patients are at low, but not
zero, risk for spontaneous arrhythmic events. The risk for an
arrhythmic event in this group has been estimated around
10% between birth and age 40 in the absence of therapy.
13
A
major risk factor for patients with asymptomatic genetically
diagnosed LQTS comes from drugs that block the I
Kr
current
and by conditions that lower their plasma potassium level.
Among genotyped patients, LQT1 males, who are asympto-
matic at a young age,
37
are at low risk of becoming
symptomatic later on in life, while females, and especially
LQT2 females, remain at risk even after age 40.
Management
The aggressiveness to manage patients with LQTS is related in
part to the risk for life-threatening arrhythmic events, as
highlighted in Section 2.5. The AHA/ACC/ESC Guidelines
for LQTS Therapy, published in 2006, are still relevant in
2012.
2
Life-style modifications such as avoidance of strenuous
exercise, especially swimming, without supervision in LQT1
patients, reduction in exposure to abrupt loud noises (alarm
clock, phone ringing, etc) in LQT2 patients, and avoidance of
drugs that prolong QT interval in all LQTS patients, should be
routine. Participation of LQTS patients in competitive sports is
still a matter of debate among the experts. Recently available
retrospective data suggest that participation in competitive
sports of some patients with LQTS may be safe.
38
Based on
these data,
38
which still need confirmation, low-risk patients,
with genetically confirmed LQTS but with borderline QTc
prolongation, no history of cardiac symptoms, and no family
Heart Rhythm, Vol 0, No 0, Month 20134

history of multiple sudden cardiac deaths (SCD), may be
allowed to participate in competitive sports in special cases
after full clinical evaluation, utilization of appropriate LQTS
therapy and when competitive activity is performed where
automated external defibrillators are available and personnel
trained in basic life support.
38
This applies especially to
patients genotyped as non-LQT1. In all patients with a high
perceived risk (see Section 2.5) and in patients with exercise-
induced symptoms, competitive sport should be avoided.
Specific therapies available for patients with LQTS and
indications for their use are described below.
Beta-blockers
Beta-blockers are clinically indicated in LQTS, including
those with a genetic diagnosis and normal QTc, unless there
is a contraindication such as active asthma.
34,35
Presently,
there is no substantial evidence to favor cardioselective or
noncardioselective beta-blockers; however, the former is
preferred in those patients who suffer from asthma. Long-
acting beta-blockers such as nadolol or sustained-release
propranolol should be preferred as these medications can be
given once or twice a day with avoidance of wide fluctua-
tions in blood levels. Recent data also suggest that, partic-
ularly in symptomatic patients, these drugs may perform
better than, for example, metoprolol.
39
While studies are not
available to define the most effective dosage, full dosing for
age and weight, if tolerated, is recommended. Abrupt
discontinuation of beta-blockers should be avoided as this
may increase the risk of exacerbation.
Implantable Cardioverter-Defibrillator (ICD) (Figure 1)
ICD therapy is indicated in LQTS patients who are resusci-
tated from cardiac arrest.
40
ICD is often favored in patients
with LQTS-related syncope who also receive beta-
blockers.
41
Prophylactic ICD therapy should be considered
in very-high-risk patients such as symptomatic patients with
two or more gene mutations, including those with the Jervell
and Lange-Nielsen variant with congenital deafness.
25
ICD
therapy has life-time implications. Complications are not
infrequent, especially in the younger age group, and risk/
benefit considerations should be carefully considered before
initiating this invasive therapy.
42,43
Accordingly, LQT1
patients who experience a cardiac arrest while not receiving
beta-blockers may only be treated with beta-blockers or with
LCSD (see below) in settings when the implant of an ICD is
likely to be associated with high risk, such as in infants and
pediatric patients.
44,45
LQTS-related sudden death in one
family member is not an indication for ICD in surviving
affected family members unless they have an individual
profile of high risk for arrhythmic events.
46
Considering the potential complications associated with
the implantation of an ICD in young individuals, we
recommend caution when using a device in asymptomatic
patients. We suggest that ICD therapy not be used as first-
line therapy in an asymptomatic LQTS patient; beta-blockers
remain the first-line therapy in LQTS patients. However, an
ICD may be considered in those patients who are deemed to
be at very high risk, especially those with a contraindication
to beta-blocker therapy. A decision to have an ICD
implanted should be made only after a careful consideration
of (1) risk of sudden death; (2) the short- and long-term risks
of ICD implantation; and (3) values and preferences of the
patient. The physician must discuss the risks and benefits of
ICD therapy with the patient, and patient’s values and
preferences are important in this decision.
Whenever ICD therapy is chosen, thoughtful program-
ming (in particular to prevent inappropriate shocks) is
pertinent and usually requires a VF-only zone, with a cutoff
rate greater than 220–240 bpm.
Left Cardiac Sympathetic Denervation (LCSD)
This procedure is often effective in reducing the probability for
arrhythmic events in high-risk patients, including those who are
intolerant of or refractory to beta-blockers alone.
47
The
procedure can be done surgically through a left supraclavicular
incision
48–50
or as a minimally invasive procedure in experi-
enced centers.
51
This procedure is frequently used in very-high-
risk infants and children in whom ICD therapy may be
relatively contraindicated due to the physical size of the patient,
in some patients with syncope despite beta-blocker therapy, and
in patients with asthma or who are intolerant of beta-blockers.
Other therapies: Gene-specific LQTS therapies including
oral mexiletine,
52
flecainide,
53
and ranolazine
54
have been
utilized to a limited extent in high-risk LQTS patients
refractory to beta-blockers or in patients with recurrent events
despite ICD and LCSD therapies. The use of these sodium
channel blockers has generally been limited to LQT3 patients.
In brief, the use of these agents is usually carried out on an
observational trial basis, with, occasionally, some dramatic
results for individual subjects. Follow-up experience with
these therapies is limited. No general recommendations can
be made at this time in the use of gene-specific therapies.
Figure 1 Consensus recommendations for ICDs in patients diagnosed
with long QT syndrome.
5Priori et al Expert Consensus Statement on Inherited Primary Arrhythmia Syndromes

3. Brugada Syndrome (BrS)
Expert Consensus Recommendations on Brugada Syndrome
Diagnosis
1. BrS is diagnosed in patients with ST-segment elevation with
type 1 morphology ≥2mmin≥1 lead among the right
precordial leads V
1
,V
2
, positioned in the 2nd, 3rd or 4th
intercostal space occurring either spontaneously or after
provocative drug test with intravenous administration of
Class I antiarrhythmic drugs.
2. BrS is diagnosed in patients with type 2 or type 3 ST-
segment elevation in ≥1 lead among the right precordial
leads V
1
,V
2
positioned in the 2nd, 3rd or 4th intercostal
space when a provocative drug test with intravenous
administration of Class I antiarrhythmic drugs induces a
type I ECG morphology.
Expert Consensus Recommendations on Brugada Syndrome
Therapeutic Interventions
Class I 1. The following lifestyle changes are recommended
in all patients with diagnosis of BrS:
a) Avoidance of drugs that may induce or
aggravate ST-segment elevation in right precor-
dial leads (for example, visit Brugadadrugs.org),
b) Avoidance of excessive alcohol intake.
c) Immediate treatment of fever with
antipyretic drugs.
2. ICD implantation is recommended in patients
with a diagnosis of BrS who:
a) Are survivors of a cardiac arrest and/or
b) Have documented spontaneous sustained VT
with or without syncope.
Class IIa 3. ICD implantation can be useful in patients with
a spontaneous diagnostic type I ECG who have
a history of syncope judged to be likely caused
by ventricular arrhythmias.
4. Quinidine can be useful in patients with a
diagnosis of BrS and history of arrhythmic
storms defined as more than two episodes of
VT/VF in 24 hours.
5. Quinidine can be useful in patients with a
diagnosis of BrS:
a) Who qualify for an ICD but present a
contraindication to the ICD or refuse it and/or
b) Have a history of documented supraventri-
cular arrhythmias that require treatment.
6. Isoproterenol infusion can be useful in
suppressing arrhythmic storms in BrS patients.
Class IIb 7. ICD implantation may be considered in patients
with a diagnosis of BrS who develop VF during
programmed electrical stimulation (inducible
patients).
8. Quinidine may be considered in asymptomatic
patients with a diagnosis of BrS with a
spontaneous type I ECG.
9. Catheter ablation maybeconsideredin patients
with a diagnosis of BrS and history of arrhythmic
storms or repeated appropriate ICD shocks.
Class III 10. ICD implantation is not indicated in
asymptomatic BrS patients with a drug-
induced type I ECG and on the basis of a
family history of SCD alone.
Epidemiology
No precise data are available on the epidemiology of BrS.
However, its prevalence is much higher in Asian and
Southeast Asian countries, especially Thailand, Philippines
and Japan, reaching 0.5–1 per 1000.
55
In some part of Asia,
BrS seems to be the most common cause of natural death
in men younger than 50 years. BrS is known as Lai Tai
(Thailand), Bangungut (Philippines), and Pokkuri (Japan).
The reason for this higher prevalence in Asia is unknown.
However, it has been speculated that it may be in part related
to an Asian-specific sequence in the promoter region of
SCN5A.
56
BrS is 8–10 times more prevalent in males than in
females.
55
The presence of a more prominent transient
outward current (I
to
) in males may contribute to the male
predominance of the syndrome.
57
Higher testosterone
levels also may have a significant role in the male
predominance.
58
Genetic basis
Inheritance of BrS occurs via an autosomal dominant mode
of transmission. Twelve responsible genes have been
reported so far.
59
In all 12 genotypes, either a decrease in
the inward sodium or calcium current or an increase in one of
the outward potassium currents has been shown to be
associated with the BrS phenotype. Genetic abnormalities
are found in one third of genotyped BrS patients. SCN5A, the
gene that encodes for the αsubunit of the cardiac sodium
channel, account for less than 30% of clinically diagnosed
BrS patients. Genetic testing is not recommended in the
absence of a diagnostic ECG. Genetic testing may be useful
otherwise and is recommended for family members of a
successfully genotyped proband.
1
Clinical manifestations
Symptoms associated with BrS include:
1. VF or aborted SCD (more often at night than during
the day)
2. Syncope
3. Nocturnal agonal respiration
4. Palpitations
5. Chest discomfort
These symptoms often occur during rest or sleep, during
a febrile state or with vagotonic conditions, but rarely
during exercise. The syndrome typically manifests during
Heart Rhythm, Vol 0, No 0, Month 20136

adulthood, with a mean age of sudden death of 41 ⫾15
years.
55
BrS is associated with no clearly apparent struc-
tural heart diseases; however, several clinical studies have
reported mild right and left ventricular structural
abnormalities.
60,61
Diagnosis
Diagnostic criteria from the Report of the Second Consensus
Conference in 2005 have been used for the diagnosis of
BrS.
55
Since some clinical studies on the sensitivity and the
specificity of the ECG diagnosis of BrS have been reported,
new diagnostic criteria of BrS are proposed here. BrS is
definitively diagnosed when a type I ST-segment elevation
is observed either spontaneously or after intravenous
administration of a sodium channel blocking agent (ajma-
line, flecainide, pilsicainide, or procainamide) in at least one
right precordial lead (V
1
and V
2
),
62
which are placed in a
standard or a superior position (up to the 2nd intercostal
space).
63,64
The differential diagnosis includes a number of diseases
and conditions that can lead to Brugada-like ECG abnormal-
ity, including atypical right bundle branch block (RBBB), left
ventricular hypertrophy, early repolarization, acute pericardi-
tis, acute myocardial ischemia or infarction, acute stroke,
pulmonary embolism, Prinzmetal angina, dissecting aortic
aneurysm, various central and autonomic nervous system
abnormalities, Duchenne muscular dystrophy, thiamine defi-
ciency, hyperkalemia, hypercalcemia, arrhythmogenic right
ventricular cardiomyopathy (ARVC), pectus excavatum,
hypothermia, and mechanical compression of the right
ventricular outflow tract (RVOT) as occurs in mediastinal
tumor or hemopericardium.
55,65
Many subjects displaying a type I ECG, spontaneous or
drug-induced, are asymptomatic. In asymptomatic patients,
the following findings are considered supportive for the
diagnosis of BrS:
1. Attenuation of ST-segment elevation at peak of exercise
stress test followed by its appearance during recovery
phase.
66,67
It should be noted, however, that in selected
BrS patients, usually SCN5A mutation-positive patients, it
has been observed that ST-segment elevation might
become more evident during exercise.
66
2. Presence of first-degree atrioventricular (AV) block and
left-axis deviation of the QRS
3. Presence of atrial fibrillation
4. Signal-averaged ECG; late potentials
68
5. Fragmented QRS
69,70
6. ST-T alternans, spontaneous left bundle branch block
(LBBB) ventricular premature beats (VPB) during
prolonged ECG recording
7. Ventricular effective refractory period (ERP) o200 ms
recorded during electrophysiological study (EPS)
70,71
and
HV interval 460 ms
8. Absence of structural heart disease including myocardial
ischemia
Prognosis and risk stratification
Since the first reporting, the reported annual rate of events
has decreased.
70,72–78
The change probably reflects the
inherent bias during the first years following the description
of a novel disease, in which particularly severe forms of the
disease are most likely to be diagnosed.
Several clinical variables havebeendemonstratedtopredict
a worse outcome in patients with BrS. Little controversy exists
on the high risk of recurrence of cardiac arrest among patients
who have survived a first VF. There is general agreement that
these patients should be protected with an ICD, irrespective of
the presence of other risk factors.
55
Most studies have concurrently agreed on the evidence that
the presence of syncopal episodes in patients with a sponta-
neous type I ECG at baseline (without conditions known to
unmask the signature sign, i.e., drugs and fever) have high risk
of cardiac arrhythmic events at follow-up.
70,72–80
Among other risk stratification indicators, the presence of
fragmented QRS
69,70
and an effective refractory period
below o200 ms
70,71
have been recently proposed. Male
gender has consistently been shown to be associated with
more arrhythmic events.
81
Spontaneous AF, which can
appear in 10% to 53% of cases, has been shown to have
prognostic significance and has been associated with
a higher incidence of syncopal episodes and docu-
mented VF.
82,83
The risk of lethal or near-lethal arrhythmic episodes
among previously asymptomatic patients with BrS varies
according to the series: 8% event rate at 33 ⫾39 months of
follow-up reported by Brugada et al
73
; 6% event rate at
34 ⫾44 months by Priori et al
70
; 1% event rate after 40 ⫾50
months and 30 ⫾21 months of follow-up, respectively, by
Eckardt et al
76
and Giustetto et al,
84
and, finally, Probst
et al
85
reported a 1.5% event rate at 31 months of follow-up.
Although large registries agree that EPS inducibility is
greatest among BrS patients with previous sudden death or
syncope,
75,76
there is no consensus on the value of the EPS in
predicting outcome. The results published by Brugada et al
73
indicate that inducibility during EPS is an independent
predictor for arrhythmic events, and Giustetto et al
84
stressed
the negative predictive value (none of the patients with a
negative EPS developed arrhythmic events vs 15% of
patients with a positive EPS result during 30 ⫾21 months
of follow-up), while the rest of the registries failed to
demonstrate this.
75,76,85
The PRELUDE (PRogrammed
ELectrical stimuLation preDictive valuE) registry failed to
support the view that lack of inducibility has negative
predictive value in BrS.
70
The FINGER (France, Italy,
Netherlands, GERmany) registry, the largest series of BrS
patients published so far, found that inducibility of sustained
ventricular arrhythmias was significantly associated with a
shorter time to first arrhythmic event in the univariate
analysis, but in the multivariate analysis, inducibility did
not predict arrhythmic events.
85
These results were con-
firmed in a recent prospective study in previously asympto-
matic patients.
70
Neither a positive family history of sudden
death nor a SCN5A mutation has proven to be a risk marker
7Priori et al Expert Consensus Statement on Inherited Primary Arrhythmia Syndromes

in any of the large studies.
75,76,81
However, some specific
types of mutations, such as those that result in a truncated
protein, or some common SNPs, might have prognostic
significance.
86–89
Therapeutic options and recommendations
for BrS patients
ICD (Figure 2)
To date, the only proven effective therapeutic strategy for the
prevention of SCD in BrS patients is the ICD. It is important
to remark that ICDs are not free from several disadvantages,
especially in the group of patients who are active young
individuals, who will require multiple device replacements
during their life-time. Some series have reported low rates of
appropriate shocks (8%–15%, median follow-up 45 months)
and high rates of complications, mainly inappropriate shocks
(20%–36% at 21–47 months follow-up).
2,90,91
Asymptomatic
BrS patients do not qualify for an ICD as their risk for life-
threatening events is very low.
59
In this group of patients,
individual assessment of associated risk factors (gender, age,
baseline ECG, inducibility) should be performed.
Pharmacological Treatment in BrS
With the objective of rebalancing the ionic currents affected
in BrS during the cardiac action potential, drugs that inhibit
the transient outward potassium current (I
to
) or increase the
sodium
þ
and calcium currents have been tested in BrS:
Isoproterenol (which increases the L-type calcium
current), has proved to be useful for treatment of electrical
storm in BrS,
92
but controlled data on its therapeutic role
are not available.
Quinidine, a Class Ia antiarrhythmic drug with I
to
and I
Kr
blocker effects, has been shown to prevent induction of VF
and suppress spontaneous ventricular arrhythmias in a clinical
setting. Quinidine is currently being used in (1) patients with
ICD and multiple shocks; (2) cases in which ICD implantation
is contraindicated; or (3) for the treatment of supraventricular
arrhythmias.
93
It has been suggested that quinidine could also
be useful in children with BrS, as a bridge to ICD or as an
alternative to it.
94,95
Randomized studies on the use of
quinidine, however, have not been performed.
Radiofrequency Catheter Ablation in BrS
After the demonstration that VF events were triggered by
ventricular ectopy of similar morphology, radiofrequency
ablation of ventricular ectopy has been postulated as a
therapeutic approach in BrS patients. Few anecdotal cases
in high-risk BrS implanted with an ICD have shown no
short-term recurrence of VF, syncope or SCD.
96–99
Nade-
manee et al
100
have presented the first series showing that
electrical epicardial substrate ablation in the RVOT can
prevent VF inducibility in a high-risk population. However,
randomized data on the effect of catheter ablation on
spontaneous arrhythmic events are lacking.
4. Catecholaminergic Polymorphic Ventricular
Tachycardia (CPVT)
Expert Consensus Recommendations on CPVT Diagnosis
1. CPVT is diagnosed in the presence of a structurally
normal heart, normal ECG, and unexplained exercise or
catecholamine-induced bidirectional VT or polymorphic
ventricular premature beats or VT in an individual o40
years of age.
2. CPVT is diagnosed in patients (index case or family
member) who have a pathogenic mutation.
3. CPVT is diagnosed in family members of a CPVT in-
dex case with a normal heart who manifest exercise-
induced premature ventricular contractions (PVCs) or
bidirectional/polymorphic VT.
4. CPVT can be diagnosed inthepresenceofastructurally
normal heart and coronary arteries, normal ECG, and
unexplained exercise or catecholamine-induced
bidirectional VT or polymorphic ventricular premature
beats or VT in an individual 440 years of age.
Expert Consensus Recommendations on CPVT Therapeutic
Interventions
Class I 1. The following lifestyle changes are recom-
mended in all patients with diagnosis of
CPVT:
a) Limit/avoid competitive sports,
b) Limit/avoid strenuous exercise,
c) Limit exposure to stressful environments.
2. Beta-blockers are recommended in all
symptomatic patients with a diagnosis of CPVT.
Figure 2 Consensus recommendations for ICDs in patients diagnosed
with Brugada syndrome.
Heart Rhythm, Vol 0, No 0, Month 20138

3. ICD implantation is recommended in patients
with a diagnosis of CPVT who experience
cardiac arrest, recurrent syncope or polymorphic/
bidirectional VT despite optimal medical
management, and/or LCSD.
Class IIa 4. Flecainide can be a useful addition to beta-
blockers in patients with a diagnosis of
CPVT who experience recurrent syncope or
polymorphic/bidirectional VT while on beta-
blockers.
5. Beta-blockers can be useful in carriers of a
pathogenic CPVT mutation without clinical
manifestations of CPVT (concealed mutation-
positive patients).
Class IIb 6. LCSD may be considered in patients with a
diagnosis of CPVT who experience recurrent
syncope or polymorphic/bidirectional VT/
several appropriate ICD shocks while on beta-
blockers and in patients who are intolerant or
with contraindication to beta-blockers.
Class III 7. ICD as a standalone therapy is not indicated in an
asymptomatic patient with a diagnosis of CPVT.
8. Programmed electrical stimulation is not
indicated in CPVT patients.
Introduction
CPVT is a rare arrhythmogenic disorder characterized by
adrenergic-induced bidirectional and polymorphic VT.
101,102
Epidemiology
The prevalence of the disease could be as high as 0.1:1000.
However, the number is a rough estimate and is not derived
from a systematic assessment in the population. Given that
the resting ECG is normal in CPVT patients and cardiac
imaging is also unremarkable, it is not easy to evaluate the
prevalence of the disease in the population. As a result, the
real prevalence of the disease is unknown.
Genetic variants
Two types of CPVT have been identified: an autosomal
dominant form, due to mutations in the gene encoding for
the cardiac ryanodine receptor (RyR2)
103,104
known as CPVT1,
and a less common autosomal recessive form, resulting from
mutations in the gene for cardiac calsequestrin (CASQ2),
105,106
now known as CPVT2. Altogether mutations in RyR2
107
and
CASQ2 are found in only 60% of the CPVT patients,
1
suggesting that other genes may be involved in CPVT.
Mutations in the KCNJ2 gene encoding the cardiac inward
rectifier K channel are known to cause the Andersen-Tawil
syndrome, also known as LQT7. Mutations in this gene have
recently been found in patients with adrenergically mediated
bidirectional VT. It is currently unknown whether these cases
should be regarded as variants of LQT7 that phenocopy CPVT
or whether specific mutations in the KCNJ2 gene cause a novel
variant of CPVT.
108
In 2007 a consanguineous Arab family
with an early-onset lethal form of recessive CPVT was linked
to a new locus on chromosome 7p1422-p22; until now,
however, no gene has been identified.
109
Mutations in the Ank2 gene are known to cause LQT4.
Recently, mutations in this gene have also been described in
a patient with bidirectional VT.
110
In analogy to the
discussion about the mutations in the KCNJ2 gene, it is
unclear whether Ank2 should be regarded as a CPVT gene or
whether LQT4 may phenocopy CPVT. Three mutations with
recessive inheritance were recently identified in two families
with cardiac arrhythmias and sudden death.
111
However,
more data are required before it becomes established whether
TRDN, which encodes triadin, is a gene for this novel form of
recessive CPVT. Finally, a mutation in the CALM1 gene
encoding for calmodulin kinase has been observed co-
segregating with adrenergically mediated arrhythmias in
one large family, and a second mutation in the same gene
was found in a sporadic patient with CPVT diagnosis.
112
Clinical manifestations
The first clinical episode often manifests in the first or second
decade of life and is usually prompted by physical activity or
emotional stress.
102,113,114
When the fainting episode is
associated with seizure-like activity it may be attributed to
a neurologic diagnosis, thus causing delay in the diagnosis of
CPVT. A family history of exercise-related syncope, seizure
or sudden death is reported in 30% of the patients and may
help directing diagnosis toward CPVT.
Diagnosis
CPVT patients present a normal resting ECG, occasionally
with a lower than normal heart rate.
102,115
When patients start
exercising ventricular ectopy develops, increasing in complex-
ity as the heart rate increases. Indeed, initially monomorphic
VPBs appear and they may be followed by polymorphic
VPBs and bidirectional or polymorphic VT. Holter monitor-
ing, exercise stress test or implantable loop recorders are
therefore pivotal investigations for establishing the diagnosis
of CPVT. Adrenergically mediated atrial arrhythmias (pre-
mature atrial beats, atrial tachycardias and atrial fibrillation)
are also common manifestations of the disease.
Programmed electrical stimulation has no diagnostic or
prognostic value in CPVT as either bidirectional or poly-
morphic VT is not inducible. Drug challenge with epinephr-
ine or isoproterenol may elicit arrhythmias and is useful in
patients who are unable to exercise (for example, after
resuscitation or because of young age). Exercise-induced
atrial arrhythmias, including atrial fibrillation, are part of the
clinical phenotype of CPVT.
116,117
Risk stratification
There are not many indicators of risk of adverse outcome in
CPVT. The occurrence of cardiac arrest before diagnosis, but
not the occurrence of syncope, is associated with higher risk
of arrhythmic episodes at follow-up.
115
Similarly, diagnosis
in childhood is a predictor of adverse outcome. After
9Priori et al Expert Consensus Statement on Inherited Primary Arrhythmia Syndromes

diagnosis, the lack of beta-blocker therapy and the use of
beta-blockers other than nadolol are independent predictors
for arrhythmic events.
115
Also, the persistence of complex
ectopy in exercise tests is a marker for worse outcome.
115
Initial evidence of genotype–phenotype correlations are
emerging in CPVT patients. Relatives with a RYR2 mutation
in the C-terminal channel-forming domain showed an
increased odds of nonsustained VT (odds ratio, 4.1; 95%
CI, 1.5–11.5; P¼.007) compared with N-terminal
domain.
118
In the recessive form of CPVT, affected individ-
uals carry homozygous or compound heterozygous muta-
tions; the carriers of a single CASQ2 mutation are healthy.
119
Nevertheless, several clinical investigations suggested that a
single CASQ2 mutation could represent a potential suscept-
ibility factor for ventricular arrhythmias.
120–122
Management
Beta-blockers
The first-line therapeutic option for patients with CPVT is
beta-blockers without intrinsic sympathomimetic activity
combined with exercise restriction.
Nadolol, being a long-acting drug, is preferred for
prophylactic therapy and has been found to be clinically
effective. The dosage used is usually high (1–2 mg/kg) with
the necessity of a faultless compliance to the therapy. The
annual rate of arrhythmic events on beta-blockers ranges
between 11% per year to 3% per year (27% over 8 years).
115
Larger groups of CPVT probands are needed to address the
issue of beta-blocker efficacy in CPVT. As nadolol is not
available in several countries it may be suggested that other
nonselective beta-blockers are equally effective (i.e., propra-
nolol). Holter recordings and exercise tests should be
repeated periodically to assure that the degree of sinus
tachycardia that precedes onset of arrhythmias is known so
that in daily life it can be avoided as much as possible.
Moreover, to prevent noncompliance-related SCD, it is
crucial to alert the patients of the importance of adherence
to therapy to preempt life-threatening events.
Asymptomatic VPBs usually persist on Holter recordings
(and exercise tests) with an unmodified threshold of appear-
ance. Complete suppression of asymptomatic VPBs does not
seem to be mandatory. The presence of couplets or more
successive VPBs during exercise testing seems significantly
associated with future arrhythmic events, suggesting inten-
sifying the treatment in these patients.
115
ICD
An ICD should be considered in CPVT patients who do not
respond to an optimal medical management and when LCSD
is not possible. All efforts should be made to ensure that
patients with an ICD have also an optimal medical treat-
ment.
123,124
In patients who have experienced an aborted
cardiac arrest before initiation of therapy, beta-blockers, or
beta-blockers and flecainide, should be started and ICD
implanted.
Implantation of an ICD is a technical challenge in pediatric
patients, and problems such as inappropriate shocks, proar-
rhythmic effects of the ICD and the need for a life-time
protection requiring multiple reinterventions should be
addressed when the decision is taken. Painful shocks by
ICD can increase the sympathetic tone and trigger further
arrhythmias leading to a malignant cycle of ICD shocks and
even death. Because of this the ICD should be programmed
with long delays before shock delivery and high cutoff rates.
Verapamil
Verapamil has been shown to be beneficial in some CPVT
patients by reducing the ventricular arrhythmia burden on top of
beta-blocker therapy during a short-term follow-up
period,
125,126
though its long-term effect remains controversial.
Flecainide
Flecainide reduces significantly the ventricular arrhythmia
burden in a limited number of CPVT patients.
127,128
A larger
study is required to fully elucidate the effect of the drug, but
flecainide should now be regarded as the first addition to beta-
blockers when control of arrhythmias seems incomplete.
Left Cardiac Sympathetic Denervation (LCSD)
Small series have been published reporting significant results
of LCSD on arrhythmic events.
50,51,129–133
Although the
short-term results seem encouraging, more data with a long-
term follow-up are needed. LCSD is not available in many
centers all over the world as it requires a very well-trained
surgeon and dedicated techniques. Therefore, the place of
LCSD in the therapeutic management of CPVT patients
resistant to optimal pharmacological therapy remains to be
proven but seems very promising.
Catheter Ablation
Catheter ablation of the bidirectional VPBs that trigger VF
may become an adjunctive therapy in patients with refractory
CPVT. However, the published experience is very limited
and therefore is not discussed in the recommendation.
134
Evaluation of family members
Family screening (siblings and parents) by clinical evalua-
tion and genetic testing (when a mutation has been detected)
is mandatory to identify undiagnosed patients and asympto-
matic carriers who are at risk of arrhythmic events and
should be treated. It is suggested that genetically positive
family members should receive beta-blockers even after a
negative exercise test.
115,118
5. Short QT Syndrome (SQTS)
Expert Consensus Recommendations on Short QT Syn-
drome Diagnosis
1. SQTS is diagnosed in the presence of a QTc ≤330 ms.
2. SQTS can be diagnosed in the presence of a QTc o360
ms and one or more of the following: a pathogenic
Heart Rhythm, Vol 0, No 0, Month 201310

mutation, family history of SQTS, family history of
sudden death at age ≤40, survival of a VT/VF episode
in the absence of heart disease.
Expert Consensus Recommendations on Short QT Syn-
drome Therapeutic Interventions
Class I 1. ICD implantation is recommended in symp-
tomatic patients with a diagnosis of SQTS who
a. Are survivors of a cardiac arrest and/or
b. Have documented spontaneous sustained VT
with or without syncope.
Class IIb 2. ICD implantation may be considered in
asymptomatic patients with a diagnosis of
SQTS and a family history of SCD.
3. Quinidine may be considered in asymptomatic
patients with a diagnosis of SQTS and a family
history of SCD.
4. Sotalol may be considered in asymptomatic
patients with a diagnosis of SQTS and a
family history of SCD.
Epidemiology and genetic bases
One of the rarer cardiac channelopathies is the short QT syndrome
(SQTS). As the terminology implies the signature sign of this
disease entity is a short QT interval. Gussak et al
135
were the first
to suggest an association with atrial and ventricular fibrillation
(i.e., SCD). With more case reports halfway through the first
decade of this century this association became clearer,
136–138
but
more than 10 years after the first description, the largest series
described contain at most 60 cases, underlining the fact that the
disease entity is rare indeed.
139
Until now DNA variants in 3
potassium channel genes (KCNH2, KCNQ1, KCNJ2) have been
described to associate with SQTS
137,138,140
; interestingly muta-
tions in these three genes are also linked with three variants of
LQTS (LQT1, LQT2, and LQT7, respectively). While mutations
found in the three genes in LQTS patients cause a loss of the
protein function, the mutations found in SQTS patients cause a
gain of function. Mutations in the genes encoding alpha- and beta-
subunits of the L-type cardiac calcium channel (CACNA1C and
CACNB2) have been identified in patients with short QT interval.
Often patients with mutations in these genes present a type I
Brugada syndrome ECG either spontaneously or in response to
drug challenge with Class I antiarrhythmic agents.
141
Clinical diagnosis
The diagnosis of SQTS is still a matter of debate. A major point
of discussion in the definition of diagnostic criteria is represented
by the cutoff value at the lower end of the QTc that should be
used to diagnose the disease. QTc should be calculated avoiding
tachycardia and bradycardia to prevent the use Bazett’sformula
at rates in which its correction is not linear and may lead to
underestimation or overestimation of QTc values.
The proposed diagnostic scoring scheme that has been put
forward by Gollob et al,
142
has not been accepted unan-
imously.
143,144
In analogy to the Schwartz score for the
LQTS the score uses a number of clinical criteria with a
gradual score for the QTc interval and a significant role for
clinical and genetic criteria.
This group has reached a consensus that a cutoff value
≤330 ms should be used for the diagnosis. Gollob et al
142
in
their “diagnostic score”also used 330 ms as the cutoff with
the heaviest weight. This QTc value is well below the
2 standard deviations (⫾350 ms in males and ⫾365 ms in
females).
145–147
In the Finnish cohort reported by Anttonen
et al
148
only 0.4% of individuals had a QTc o340 ms and
0.1% of the population had a QTc o320 ms.
Risk stratification and treatment
Therapeutic management using ICDs is undisputed in SQTS
patients who have experienced sustained VT/VF episodes.
139
Appropriate programming of the ICD is needed to prevent
inappropriate ICD shocks from T-wave oversensing due
to tall T waves. Quinidine seems an effective alternative due
to the QT-prolonging action. However, it has been reported
that the QTc-prolonging effect of quinidine is particularly
prominent in patients with a KCNH2 mutation (SQTS type
I).
139,149
Other drugs, including Class III drugs, such as
sotalol, are not effective in prolonging the QTc interval in
SQT1 patients
149
but may be effective in the other subtypes.
The optimal strategy for primary prevention of cardiac
arrest in SQTS is not clear given the lack of independent risk
factors, including syncope, for cardiac arrest. Although
intuitively it might seem reasonable to suggest that patients
with the shortest QTc values are at highest risk, clinical data
do not support this hypothesis.
139
However, in a combined
symptomatic and asymptomatic group (QTc o360 ms) QTc
was the only risk factor for arrhythmic events.
139
Quinidine might have a role in primary prevention of
cardiac arrest, but data are very preliminary and require
confirmation in larger cohorts of patients. There are certainly
no data to support the implantation of an ICD in asympto-
matic patients with SQTS. A study from Finland revealed
that individuals with short (o340 ms) and very short
(o320 ms) QTc values had no documented arrhythmic
events after an average follow-up of 29 years.
148
Data from
Japan and the US seem to support these findings.
145,150
An
ICD might be considered in SQTS patients with a strong
family history of SCD and evidence for abbreviated QTc in
at least some of the victims.
6. Early Repolarization (ER)
Expert Consensus Recommendations on Early Repolariza-
tion Diagnosis
1. ER syndrome is diagnosed in the presence of J-point
elevation ≥1mmin≥2 contiguous inferior and/or
lateral leads of a standard 12-lead ECG in a
patient resuscitated from otherwise unexplained VF/
polymorphic VT
2. ER syndrome can be diagnosed in an SCD victim with a
negative autopsy and medical chart review with a
previous ECG demonstrating J-point elevation ≥1mm
11Priori et al Expert Consensus Statement on Inherited Primary Arrhythmia Syndromes

in ≥2 contiguous inferior and/or lateral leads of a standard
12-lead ECG
3. ER pattern can be diagnosed in the presence of
J-point elevation ≥1mmin≥2 contiguous inferior and/
or lateral leads of a standard 12-lead ECG
Expert Consensus Recommendations on Early Repolariza-
tion Therapeutic Interventions
Class I 1. ICD implantation is recommended in patients
with a diagnosis of ER syndrome who have
survived a cardiac arrest.
Class IIa 2. Isoproterenol infusion can be useful in suppres-
sing electrical storms in patients with a diag-
nosis of ER syndrome.
3. Quinidine in addition to an ICD can be useful
for secondary prevention of VF in patients with
a diagnosis of ER syndrome.
Class IIb 4. ICD implantation may be considered in
symptomatic family members of ER syndrome
patients with a history of syncope in the
presence of ST-segment elevation 41mmin
2 or more inferior or lateral leads.
5. ICD implantation may be considered in
asymptomatic individuals who demonstrate a
high-risk ER ECG pattern (high J-wave
amplitude, horizontal/descending ST segment) in
the presence of a strong family history of juvenile
unexplained sudden death with or without a
pathogenic mutation.
Class III 6. ICD implantation is not recommended asymp-
tomatic patients with an isolated ER ECG
pattern.
Definition and epidemiology
In 1953, Osborn described the classic J wave in experimental
hypothermia.
151
Dogs subjected to hypothermia developed
spontaneous VF that was preceded by the development of J
waves.
151
The J wave, which was attributed to a current of
injury (hence the term “J”) was later termed the Osborn
wave. Further experiments demonstrated that hypothermic J
waves are presumably the ECG reflection of increased
dispersion of repolarization caused by a disproportionate
abbreviation of the epicardial action potential compared to
the endocardium.
152
ER is a common ECG pattern characterized by J-point and
ST-segment elevation in 2 or more contiguous leads. The
presence of ER pattern in the precordial leads has been
considered a benign phenomenon, but recently its presence in
the inferior and/or lateral leads has been associated with
idiopathic VF in case-control studies (ER syndrome).
153–158
Furthermore, the ER ECG pattern is associated with an
increased risk of arrhythmic death and mortality in epidemio-
logical studies, either as a primary cause of sudden death or in
conjunction with concurrent cardiac disease.
159–162
Numerous cases of patients with idiopathic VF who have
the ER pattern in the inferior and/or lateral ECG leads have
now been described. At least five case-control studies assess-
ing the presence of ER among patients with idiopathic VF,
involving more than 300 patients, have been published.
153–158
ER ECG pattern (41 mm) in the inferior/lateral leads occurs
in 1%–13% of the general population and in 15%–70% of
idiopathic VF cases.
153–161
In the pediatric age group it is even
more prevalent. Male sex is strongly associated with ER ECG
pattern, since over 70% of subjects with ER are males. The
prevalence of the ER ECG pattern declines in males from early
adulthood until middle age, which suggests a hormonal
influence on the presence of ER.
163
The ER pattern is more
common in young physically active individuals, athletes, and
African-Americans.
164
There is an increased prevalence of ER
reported in Southeast Asians.
161
The ER pattern is associated
with high vagal tone, as well as hypothermia and hypercalcemia.
ECG features of bradycardia, prolonged QRS duration, short QT
interval, and left ventricular hypertrophy assessed by the
Sokolow-Lyon index are also associated with ER.
163
There also
is some overlap between the BrS and ER syndrome, since an ER
pattern in the inferior or lateral leads is found in 11%–15% of the
BrS patients.
165
ER pattern also is frequently observed in
patients with short QT syndrome, and many patients with an
ER pattern or ER syndrome have a relatively short QT interval
without frank short QT syndrome.
166
Clinical diagnosis
Given the high prevalence of the ECG pattern of ER, we
recommend a conservative approach in establishing the diag-
nosis of this condition. Patients with the ER pattern on the 12-
lead ECG who have been resuscitated from an ECG-
documented episode of idiopathic VF and/or polymorphic VT
are those diagnosed with the ER syndrome. Similarly, SCD
victims with a negative autopsy with an archived ECG showing
the ER pattern also are diagnosed with ER syndrome when
evidence of other diagnoses such as BrS have been excluded.
At this stage of our understanding of early repolarization,
there is an unusual dilemma in which the ECG pattern is
highly prevalent, the inheritance is not clearly monogenic in
most cases and the genetic substrate is not clearly defined. For
this reason, we have chosen not to label family members with
the ER pattern as ER syndrome patients pending a better
understanding of their risk. High-risk features including extent
of family history of SCD, arrhythmic syncope and amplitude
and morphology of the ER pattern may lead to consideration
of a prophylactic ICD in conjunction with review by an expert
center with a focus on inherited arrhythmias. Asymptomatic
individuals with the ER pattern on ECG with a mutation
considered pathogenic for ER as well as family members of a
patient diagnosed with ER syndrome who present with a
diagnostic ECG may be affected by the disease.
Genetic variants
Genetic contributions to ER are suggested by anecdotal
observations of a common familial history of SCD of
Heart Rhythm, Vol 0, No 0, Month 201312

subjects with ER and idiopathic VF.
167
Familial ER has been
reported to have an autosomal dominant inheritance pattern
with incomplete penetrance. Two independent population-
based studies also have suggested some degree of inheritance
of the ER patterns in the general population,
163,168
but the
familial inheritance of malignant ER patterns has not been
clearly demonstrated.
153
A candidate gene approach in
idiopathic VF patients with ER has identified a mutation in
KCNJ8, which encodes a pore-forming subunit of the ATP-
sensitive potassium channel.
169,170
Mutations in the L-type
calcium channel genes, including CACNA1C, CACNB2B,
and CACNA2D1,
171
as well as loss-of-function mutations in
SCN5A
172
have also been associated with idiopathic VF with
ER. Given the high prevalence of ER in the general
population, ER likely has a polygenic basis that also is
influenced by nongenetic factors. A recent genome-wide
association meta-analysis in three independent populations
of European ancestry found eight loci associated with ER,
the strongest association being found with SNPs located at
the KCND3 genes, which encode the transient outward
potassium channel Ito (Kv4.3) coding gene.
173
However,
replication studies could not confirm these observations in
other populations so far.
Clinical manifestations
Life-threatening arrhythmias are often the first and unex-
pected manifestation of ER syndrome. An increase in the
amplitude of ER has been described before the onset of VF in
ER syndrome patients, and VF is usually triggered by short-
long-short sequence in which a short coupled extrasystolic
beat is followed by a pause and the next extrasystolic beat
falls on the T wave of the preceding beat and initiates the
arrhythmic episode.
156
The majority of population-based
studies have shown that subjects with ER in the inferior leads
are at a higher risk of all-cause mortality, cardiac mortality,
and especially unexpected sudden death,
159–162
though some
exceptions have been reported.
174
In the studies of middle-
aged subjects, the mortality curves of subjects with and
without ER begin to diverge after age 50,
159,160
suggesting
that the presence of the ER pattern may increase the risk of
arrhythmic death in the presence of additional triggers, such
as acute ischemic events.
Diagnosis
In survivors of VF and in patients with polymorphic VT,
clinical evaluation including echocardiogram, coronary
angiography, magnetic resonance imaging (MRI), and
selected endocardial biopsies should be performed to exclude
other causes of VF. Consideration should be given to
provocative drug infusion with epinephrine and with a sodium
channel blocker, such as ajmaline or flecainide, to unmask
latent inherited causes of cardiac arrest, such as BrS and
LQTS.
157
The presence of short QT syndrome also should be
noted. There are no validated techniques to provoke the ER
pattern, although 12-lead Holter monitoring to detect evidence
of the ER pattern during bradycardia is warranted.
Risk stratification
The magnitude of the J-point elevation may have prognostic
significance. Either slurred or notched J-point elevation ≥0.2 mV
is relatively rare in the general population but appears to be
associated with an increased risk.
159
Furthermore, J-point eleva-
tion in idiopathic VF patients is of greater amplitude and ECG
lead distribution compared to those with an established cause of
cardiac arrest.
157
The available data also suggest that transient
changes in the presence and amplitude of J-point elevation
portends a higher risk for VF.
153
A horizontal or descending
ST segment following J-point elevation is associated with a worse
outcome in the general population.
175
This observation has been
very helpful in distinguishing idiopathic VF patients from
matched controls and is a key aid in clinical decision making.
176
Management
The clinical implications of the observation of an ER pattern in
the ECG of an asymptomatic subject are not clear. The presence
of ER is associated with 3 times the risk of developing VF, but
the overall risk is still negligible considering the rarity of VF in
the general population.
158,177
Because the presence of ER may
increase the vulnerability to sudden death during an acute
ischemic event, a plausible implication stemming from the
population studies is that middle-aged subjects with the ER
pattern in the ECG, especially those with a high amplitude of
J-point elevation and horizontal/downsloping ST segment,
should target a reduction in their long-term risk for acute
coronary events in accordance with current practice guidelines.
Electrical storm is relatively common after ICD implan-
tation in patients with the ER syndrome.
178,179
Case series
evidence supports the acute use of isoproterenol for
suppression of recurrent VF and quinidine for long-term sup-
pression.
178,179
Isoproterenol is typically initiated at 1.0 μg/min,
targeting a 20% increase in heart rate or an absolute heart rate
490 bpm, titrated to hemodynamic response and suppression of
recurrent ventricular arrhythmia.
Screening of family members
No recommendations can be given to screen the families of
individuals with asymptomatic ER pattern. There are no
established provocative tests to diagnose concealed ER in
family members of ER syndrome patients, although prelimi-
nary observations suggest that the Valsalva maneuver may
assist in identifying concealed ER cases. Therapeutic rec-
ommendation 5 uses the term “strong family history.”There
is no clear definition of this term, but it is typically chosen
when more than one family member is affected, deaths occur
at an early age and a first-degree relative is affected.
7. Progressive Cardiac Conduction Disease
(PCCD)
Expert Consensus Recommendations on Progressive Car-
diac Conduction Disease Diagnosis
1. Progressive cardiac conduction disease (PCCD) is
diagnosed in the presence of unexplained progressive
13Priori et al Expert Consensus Statement on Inherited Primary Arrhythmia Syndromes

conduction abnormalities in young (o50 years)
individuals with structurally normal hearts in the
absence of skeletal myopathies, especially if there is a
family history of PCCD.
Expert Consensus Recommendations on Progressive Car-
diac Conduction Disease Therapeutic Interventions
Class I 1. Pacemaker implantation is recommended in
patients with a diagnosis of PCCD and the
presence of:
a) Intermittent or permanent third-degree or
high-grade AV block or
b) Symptomatic Mobitz I or II second-degree
AV block.
Class IIa 2. Pacemaker implantation can be useful in
patients with a diagnosis of PCCD and the
presence of bifascicular block with or without
first-degree AV block.
3. ICD implantation can be useful in adult patients
diagnosed with PCCD with a mutation in the
lamin A/C gene with left ventricular dysfunc-
tion and/or nonsustained VT.
Introduction
Progressive cardiac conduction disease (PCCD) is a hetero-
geneous disorder of unclear etiology, which can be serious
and potentially life-threatening. Its underlying mechanism
can be either functional or structural or there can be overlap
between these two mechanisms.
180
The most frequent form
of PCCD is a degenerative form called Lenègre-Lev disease.
The mechanism of PCCD with structural abnormality is
considered as a primary degenerative disease or an exagger-
ated aging process, with sclerosis principally affecting the
conduction tissue.
181
Aging itself is suggested to play a
critical role in PCCD, meaning that at every age conduction
abnormalities are more outspoken than expected based on
age alone.
Both familial PCCD with either a structurally normal heart
(hereby defined as “isolated PCCD”) and familial PCCD
associated with dilated cardiomyopathy will be discussed.
Epidemiology
No systematic clinical data are available on the age of onset
and course of symptoms in affected individuals. When
genetically mediated, the majority of PCCD patients have
an autosomal dominant mode of inheritance.
1
Genetic variants
The discovery of gene mutations that are causally involved in
inherited PCCD is relatively recent.
180
Common PCCD-
associated genes (defined as genes with causative mutation
in 45% of affected individuals
1
) are SCN5A and TRPM4 for
PCCD occurring in the structurally intact heart
182
and LMNA
for PCCD associated with heart failure.
1
PCCD and structurally normal heart
Mutations in the SCN5A gene cause the majority of familial
PCCD and often causes a combined phenotype with Brugada
syndrome.
181
Subtle structural abnormalities, mainly fibrosis,
are present in SCN5A mutation positive subjects. Recently,
mutations in the transient receptor potential channel, sub-
family M(elastatine), member 4 (TRPM4)Ca
2þ
-activated
channel gene were reported in patients with PCCD
183
and are
estimated to account for a significant portion of inherited
forms of RBBB (25%) or AV block (10%).
1
PCCD and structurally abnormal heart
When PCCD is accompanied by the presence of concomitant
congenital heart disease, mutations in early cardiac tran-
scription factor genes such as Nkx2.5 or GATA4 are more
likely. Mutations in Nkx2.5 or TBX5, genes involved in the
regulation of heart development, are associated with struc-
tural congenital heart defects such as septal defects.
181
PCCD also may precede development of dilated cardio-
myopathy. Mutations in the LMNA gene encoding lamin A/C
were found to be causally involved in Emery-Dreifuss
muscular dystrophy as well as in families with dilated
cardiomyopathies and severe PCCD without skeletal muscle
involvement.
180,181,184
In a small percentage of cases, Wolff-Parkinson-White
syndrome is familial and associated with cardiac hyper-
trophy, presenting as a hypertrophic cardiomyopathy pheno-
copy. Mutations in the PRKAG2 gene and other glycogen
storage diseases may also display abnormal electrical AV
connections. Patients with mutations in the PRKAG2 gene
have a variable combination of glycogen storage cardiomy-
opathy, PCCD including sinus bradycardia and AV block,
ventricular preexcitation, arrhythmias, and sudden death.
185
Most authors would classify the phenotype of PRKAG2
mutations as a hypertrophic cardiomyopathy with conduction
defects rather than a PCCD with hypertrophy.
Clinical manifestations
PCCD can be seen by a prolonged P-wave duration, PR
interval and QRS widening with axis deviation on the surface
ECG, which may progress over time as an age-dependent
penetrance. In isolated forms of PCCD, there are typically no
extracardiac manifestations. In nonisolated forms of PCCD,
congenital heart disease, cardiomyopathy, or extracardiac
manifestations are present. Phenotypic expression of muta-
tions may vary from individual to individual and has, among
others, an age-dependent onset.
1
In patients with mutations in the LMNA gene and PCCD, the
AV node and specialized conduction system are progressively
replaced by fibrofatty tissue and patients are at risk for
premature SCD.
184,185
In addition to conduction abnormalities,
most adult patients with LMNA mutations have AV conduction
disturbances, and atrial and ventricular arrhythmias.
186
LMNA
mutations are also found at frequencies of 6%–8% among
patient populations with idiopathic or familial dilated cardio-
myopathy. Heart failure is a common phenotypic feature in
Heart Rhythm, Vol 0, No 0, Month 201314

families with cardiac manifestations of LMNA disease.
187,188
Because of the limited information and the low number of
patients in many of the clinical reports, a statement about the
incidence of arrhythmias in relation to structural or functional
PCCD is precarious. The occurrence of tachyarrhythmia and
sudden death is expected to be more frequent in PCCD patients
that carry loss-of-function SCN5A mutations, a disease entity
comparable with SCN5A-associated BrS.
180
Interestingly, over-
lapping phenotypes of BrS1, LQTS, and inherited conduction
system defects have been reported in some families.
185
Diagnosis
The diagnosis of PCCD in an index patient is based on
clinical data including history, family history, and 12-lead
ECG. The potential presence of congenital heart disease and/
or cardiomyopathy must be investigated by 2-D echocar-
diography or other imaging modalities, such as cardiac MRI.
Early-onset PCCD in the absence of structural heart disease
should prompt consideration of PCCD genetic testing,
particularly if there is a positive family history of conduction
abnormalities, pacemaker implants, or sudden death.
1
(Targeted) genetic testing may be considered as part of the
diagnostic evaluation for patients with either isolated PCCD
or PCCD with concomitant structural heart disease, espe-
cially when there is documentation of a positive family
history of PCCD.
1
Risk stratification
Screening for underlying cardiovascular manifestations with
a resting 12-lead ECG, Holter, or 2-D echocardiogram is
recommended, independent of symptom status. Patients with
first-degree AV block in association with bifascicular block
and symptomatic advanced AV block have a substantial
incidence of sudden death. In the presence of permanent or
transient third-degree AV block, syncope is associated with
an increased incidence of sudden death regardless of EPS
results.
189
Based on this evidence in patients with PCCD
diagnosis, pacemaker implant may be indicated even in
individuals with bifascicular block and first-degree AV block
and thus representing an exception to the recommendation
set by international guidelines for patients who have this
phenotype in all the other clinical conditions.
There is no genotype-based risk stratification for patients
with PCCD. Some mutations may be associated with develop-
ment of heart failure and/or extracardiac features, such as
skeletal myopathy, which can be diagnosed, followed and
treated after having PCCD classified as a genetic entity.
1
Patients with LMNA mutations may experience malignant
arrhythmias and SCD despite pacemaker implantation.
184
ICD
therapy is therefore warranted at an early stage; a risk
stratification scheme has recently been proposed.
190
Management
Once cardiac involvement occurs, particularly with the muscu-
lar dystrophies, the clinician should maintain a low threshold
for investigating symptoms or ECG findings to determine the
need for EPS, pacemaker or ICD implantation. Screening for
underlying cardiovascular manifestations with a resting 12-lead
ECG or 2-D echocardiogram to determine cardiac involvement
should be part of the routine clinical assessment, independent of
symptom status.
2
Asymptomatic family members who are
positive for the family’sPCCD-associatedmutationshouldbe
prospectively followed for the early development of PCCD-
related symptoms, deterioration of cardiac conduction, and
beginning signs and symptoms of heart failure. In addition,
medications with conduction-slowing properties should be
restricted, and fever, an aggravating trigger in individuals with
SCN5A mutations, should be preemptively treated.
1
Screening of family members
Cascade family screening is useful in families with mutation-
positive PCCD. When a clinical diagnosis of PCCD is
established in an index case, a careful clinical investigation of
first-degree family members is necessary. Genotyping of family
relatives is done after mutation identification in the index cases
and may be useful to exclude presence or development of
PCCD. Taken together, a comprehensive clinical and genetic
evaluation of family members is generally recommended to
detect inherited forms of PCCD disease and other cardiac and
noncardiac disease features.
1
8. Unexplained Cardiac Arrest: Idiopathic VF
Expert Consensus Recommendations on Idiopathic Ventric-
ular Fibrillation (IVF) Diagnosis
1. IVF is defined as a resuscitated cardiac arrest victim,
preferably with documentation of VF, in whom known
cardiac, respiratory, metabolic and toxicological etiologies
have been excluded through clinical evaluation.
Expert Consensus Recommendations on Idiopathic
Ventricular Fibrillation Evaluation
Class IIa 1. Genetic testing in IVF can be useful when
there is a suspicion of a specific genetic disease
following clinical evaluation of the IVF patient
and/or family members.
Class III 2. Genetic screening of a large panel of genes in
IVF patients in whom there is no suspicion of
an inherited arrhythmogenic disease after
clinical evaluation should not be performed.
Expert Consensus Recommendations on Idiopathic
Ventricular Fibrillation Therapeutic Interventions
Class I 1. ICD implantation is recommended in patients
with the diagnosis of IVF.
Class IIb 2. Antiarrhythmic therapy with quinidine, PES guided
or empirical, maybeconsideredin patients with a
diagnosis of IVF in conjunction with ICD
implantation or when ICD implantation is
contraindicated or refused.
15Priori et al Expert Consensus Statement on Inherited Primary Arrhythmia Syndromes

3. Ablation of Purkinje potentials may be
considered in patients with a diagnosis of IVF
presenting with uniform morphology PVCs in
conjunction with ICD implantation or when
ICD implantation is contraindicated or refused.
4. If a first-degree relative of an IVF victim
presents with unexplained syncope and no
identifiable phenotype following thorough
investigation, then after careful counseling an
ICD implant may be considered.
Expert Consensus Recommendations on Idiopathic
Ventricular Fibrillation Evaluation of Family Members
Class I 1. Evaluation of first-degree relatives of all IVF
victims with resting ECG, exercise stress testing
and echocardiography is recommended. Assess-
ment of first-degree relatives with history of
palpitations, arrhythmias or syncope should be
prioritized.
2. Follow-up clinical assessment is indicated in
young family members of IVF victims who may
manifest symptoms and/or signs of the disease at
an older age and in all family members
whenever additional sudden unexplained death
syndrome (SUDS) or sudden unexplained death
in infancy (SUDI) events occur.
Class IIa 3. Evaluation of first-degree relatives of IVF victims
with Holter and signal-averaged ECGs, cardiac
MRI and provocative testing with Class Ic
antiarrhythmic drugs can be useful.
Class IIb 4. Evaluation of first-degree relatives of IVF victims
with epinephrine infusion may be considered.
Definition
When individuals survive a cardiac arrest we are able to
investigate and treat them for the underlying cause. The term
idiopathic ventricular fibrillation (IVF) is used when the cardiac
arrest remains unexplained despite this investigation. In 1992,
when discovery of the genetic basis of cardiac channelopathies
was in its infancy, the hypothesis was advanced that concealed
forms of arrhythmogenic disorders could underlie these cases
representing subclinical “electrical abnormalities”of the
heart.
191
A subsequent expert consensus statement
192
defined
IVF as “the terminology that best acknowledges our current
inability to identify a causal relationship between the clinical
circumstance and the arrhythmia.”In the same article, the
minimal requirements for the diagnosis of IVF were also
defined.
192
It is therefore expected that the proportion of cardiac
arrests defined as IVF is destined to decrease as we identify
more conditions that may lead to life-threatening arrhythmias in
the absence of overt cardiac abnormalities.
Epidemiology
In the CASPER registry of cardiac arrest survivors, in whom
overt coronary and structural disease had already been
excluded, 44% remained without a diagnosis after further
comprehensive evaluation (see below).
193
There is little
other systematic data on the prevalence of IVF as an entity.
Diagnosis
IVF is diagnosed by the exclusion by clinical evaluation of
known cardiac, respiratory, metabolic and toxicological
etiologies that may lead to cardiac arrest. Ideally VF should
be documented. The most recent consensus document
defining the minimal requirements for diagnosis of IVF dates
back to 1997. Data from the CASPER registry
193
suggest that
careful clinical assessment of patients surviving a cardiac arrest
in the absence of structural cardiac abnormalities (normal
cardiac function on echocardiogram, no evidence of coronary
artery disease, and a normal ECG) can lead to diagnosis of a
disease in more than half of cases. A staged cascade screening
approach was associated with an incremental diagnostic yield
in this cohort: (1) ECG, signal-averaged ECG, telemetry; (2)
imaging (MRI with and without contrast); (3) provocative tests
(exercise stress test, epinephrine infusion, procainamide); (4)
EPS and voltage map; (5) ventricular biopsy; and (6) targeted
genetic testing. A similar yield has been observed with
thorough evaluation of sudden unexplained death syndrome
(SUDS) cases and their relatives.
194,195
Genetic diagnostic testing in IVF cases may be considered
when clinical evaluation is either inconclusive or suggests
that a “forme fruste”of a channelopathy might be present.
Several factors may generate such a suspicion: (1) age, (2)
gender, or (3) activity at the time of cardiac arrest (for
example rest, exercise, emotion, or auditory stimuli). A
family history of premature sudden death may also strengthen
the possibility of a genetic substrate. The yield of genetic
screening of IVF patients is heterogeneous. Krahn et al
193
identified mutations in 47% of patients with suspected IVF by
using targeted genetic testing led by clinical diagnostic
testing. However, Bai et al
196
reported that the yield of
genetic screening in IVF patients and family members of
SCD victims is very low in the absence of a clinical suspicion
to guide testing. The cost of screening a large number of
genes responsible for many different diseases is too expensive
at this stage to be recommended, particularly as a negative
result does not rule them out as potential the causes of IVF.
Management
In IVF, as there is by definition no evidence for pathogenesis,
management is empirical and most patients are advised to
undergo an ICD implant. Unfortunately, the natural history of
IVF is poorly defined.Datacollectedinasmallseriesof
patients by Crijns et al
197
suggestedthatat2.8yearsoffollow-
up only 1/10 patients had a recurrence of VT but none
experienced ICD shock or death. Similarly, Belhassen and
Viskin
198
reported a multicenter experience on 26 IVF patients
studied with programmed electrical stimulation (PES) to test
VF inducibility (81% of inducible patients). PES was repeated
after administration of quinidine or a combination of quinidine
and amiodarone to test suppression of inducibility. At follow-up
ranging between 14 and 216 months no VF or fatalities
Heart Rhythm, Vol 0, No 0, Month 201316

occurred. Remme et al
199
reported a 43% recurrent event rate in
a long-term follow-up of 37 IVF patients (77 ⫾41 months).
Knechtetal
200
reported their experience in which IVF patients
with recurrent and troublesome VF underwent catheterization
and ablation of Purkinje potentials responsible for VPBs that
initiated the arrhythmia. By far the majority (36/38) were free of
VF at 52 months of follow-up. This represents a specificsubset
of IVF patients presenting with frequent ventricular arrhyth-
mias; most IVF patients do not suffer such a storm after initial
resuscitation from cardiac arrest.
Screening of family members
Experience of investigating blood relatives of IVF survivors
is limited but supports the possibility of incompletely
penetrant disease being more evident in family members
than in the index case, particularly if only limited inves-
tigation is possible due to a poor neurologic outcome post-
arrest.
193
A similar predominantly noninvasive diagnostic
protocol to that utilized in SUDS families may be employed
(see Section 9). As with families of SUDS victims, it is
reasonable that relatives of IVF survivors who are obligate
carriers or have ominous symptoms such as cardiac syncope
should be prioritized for evaluation. In families with IVF,
young family members may require periodic reassessment
even if the initial assessment is normal as young patients may
only become cognizant of symptoms at an older age, and
certain diseases have age-related penetrance. Repeated
evaluations should occur if family members become symp-
tomatic or additional suspicious sudden deaths are identified
in the family. There are no data on appropriate interventions
for a first-degree relative of an IVF victim who presents with
unexplained cardiogenic syncope without an identifiable
phenotype despite thorough investigation. Consideration
should be given to monitoring with an implantable loop
recorder or after careful counseling the possibility of an ICD
implant.
9. Unexplained Sudden Cardiac Death: Sudden
Unexplained Death Syndrome (SUDS) and
Sudden Unexplained Death in Infancy (SUDI)
Expert Consensus Recommendations on Sudden Unex-
plained Death Syndrome Diagnosis
1. It is recommended that an unexplained sudden death
occurring in an individual older than 1 year of age
is known as “sudden unexplained death syndrome”
(SUDS).
2. It is recommended that a SUDS death with negative
pathological and toxicological assessment is termed
“sudden arrhythmic death syndrome”(SADS).
Expert Consensus Recommendations on Sudden Unex-
plained Death Syndrome Evaluation
Class I 1. It is recommended that personal/family history
and circumstances of the sudden death are
collected for all SUDS victims.
2. It is recommended that all sudden death victims
diagnosed as SUDS undergo expert cardiac
pathology to rule out the presence of
microscopic indicators of structural heart
disease.
3. Collection of blood and/or suitable tissue for
molecular autopsy/postmortem genetic testing is
recommended in all SUDS victims.
Class IIa 4. An arrhythmia syndrome focused molecular
autopsy/postmortem genetic testing can be
useful for all SUDS victims.
Expert Consensus Recommendations on Sudden Unex-
plained Death Syndrome Therapeutic Interventions
Class I 1. Genetic screening of the first-degree relatives of
a SUDS victim is recommended whenever a
pathogenic mutation in a gene associated with
increased risk of sudden death is identified by
molecular autopsy in the SUDS victim.
2. Evaluation of first-degree blood relatives of all
SUDS victims with resting ECG with high right
ventricular leads, exercise stress testing and
echocardiography is recommended. Assessment
of obligate carriers and relatives with a history of
palpitations, arrhythmias or syncope should be
prioritized.
3. Follow-up clinical assessment is indicated in
young family members of SUDS victims who
may manifest symptoms and/or signs of the
disease at an older age and in all family
members whenever additional SUDS or SUDI
events occur.
Class IIa 4. Evaluation of first-degree relatives of SUDS
victims with ambulatory and signal-averaged
ECGs, cardiac MRI and provocative testing
with Class Ic antiarrhythmic drugs can be useful.
Class IIb 5. Evaluation of first-degree relatives of SUDS
victims with epinephrine infusion may be
considered.
Expert Consensus Recommendations on Sudden Unex-
plained Death in Infancy Diagnosis
1. It is recommended that unexplained sudden death occurring
in an individual younger than 1 year of age with negative
pathological and toxicological assessment is termed “sudden
unexplained death in infancy”(SUDI).
Expert Consensus Recommendations on Sudden Unex-
plained Death in Infancy Evaluation
Class I 1. It is recommended that personal/family history
and circumstances of the sudden death are
collected for all SUDI victims.
2. Collection of blood and/or suitable tissue for
molecular autopsy is recommended in all SUDI
victims.
17Priori et al Expert Consensus Statement on Inherited Primary Arrhythmia Syndromes

Class IIa 3. An arrhythmia syndrome focused molecular
autopsy/postmortem genetic testing can be
useful for all SUDI victims.
Class IIb 4. Sudden death victims diagnosed as SUDI at
autopsy may be considered for assessment by
an expert cardiac pathologist to rule out the
presence of microscopic indicators of structural
heart disease.
Expert Consensus Recommendations on Sudden Unex-
plained Death in Infancy Therapeutic Interventions
Class I 1. Genetic screening of the first-degree relatives of
a SUDI victim is recommended whenever a
pathogenic mutation in a gene associated with
increased risk of sudden death is identified by
molecular autopsy in the SUDI victim. Obligate
mutations carriers should be prioritized.
Class IIa 2. Evaluation of first-degree relatives of SUDI
victims with a family history of inherited heart
disease or other SUDS or SUDI deaths with
resting ECG and exercise stress testing and
additional tests as indicated can be useful.
Assessment of first-degree relatives with
history of arrhythmias or syncope should be
prioritized.
3. Follow-up clinical assessment can be useful in
young family members of SUDI victims with a
family history of inherited heart disease or other
SUDS or SUDI death who may manifest
symptoms and/or signs of the disease at an
older age and in all family members whenever
additional SUDS or SUDI events occur.
Class IIb 4. Evaluation of first-degree relatives of SUDI
victims with resting ECG and exercise stress
testing may be considered.
Definitions
SCD is a common outcome of “acquired”cardiac diseases
such as acute myocardial ischemia and ischemic dilated
cardiomyopathy where the cause is readily determined.
201
An unexplained SCD, however, is a pathological diagnosis
of exclusion that covers a number of possible etiologies.
A commonly used term is “sudden arrhythmic death
syndrome”(SADS), which describes a SCD where an
autopsy and toxicology have been undertaken, noncardiac
etiologies excluded and the heart found to be morphologi-
cally normal.
202,203
Another similar descriptor, “sudden
adult death syndrome,”
204
has been termed to describe
nonpediatric cases. In Southeast Asia, cases of young male
sudden deaths have been attributed to “sudden unexpected or
unexplained death syndrome”(SUDS) as well as “sudden
unexpected nocturnal death syndrome”(SUNDS). These
have, however, been directly related to BrS as an etiology,
have been used interchangeably and do not necessarily imply
a through pathological evaluation.
205
The terms “sudden
infant death syndrome”(SIDS) or “sudden unexpected death
in infancy”(SUDI) are used in cases under 1 year of age
when the cause of death remains unexplained, although
SIDS implies a more stringent circumstantial and forensic
investigation. These are discussed further below.
206
The definitions utilized for unexplained SCD have varied.
The timing of unwitnessed deaths (less than 1 hour to less
than 24 hours) is one factor.
202,203,207,208
Another is the
limited or even absence of access to autopsy in some
countries and a histopathological examination may be the
exception rather than the rule.
207,209,210
If an autopsy has not
been undertaken or considered inadequate then the death
remains unexplained, but other etiologies, genetic and
acquired, should be considered and a broader diagnostic
view needs to be considered. Consistent use of the descrip-
tors SUDS and SADS would be similar to the use of SUDI
and SIDS and will help reduce confusion over terminology.
This will ensure that familial evaluation is guided toward the
diagnosis of likely etiologies such as arrhythmia syndromes.
Epidemiology
It is clear that the relevant International Classification of Diseases
codes (ICD codes) for unexplained SCD underestimate signifi-
cantly its true frequency.
203
The incidence and prevalence of
unexplained SCD depend, however, upon the population studied
and the investigators. Autopsies for unexplained sudden death
are mandatory in the United Kingdom. The incidence of
unexplained SCD among the general population aged 4 to 64
years has been estimated to be up to 1.34/100,000 per annum,
203
with 4.1% of SCD in the 16- to 64-year age group being
unexplained.
204
A recent Irish study reported an incidence of
unexplained SCD of 0.76/100,000 year in subjects aged 14 to 35
years old accounting for 27% of the total incidence of SCD.
211
Danish data are limited by a 75% autopsy rate but supports an
incidence of at least 0.8/100,000 per annum among 1 to 35 year
olds with 43% of autopsied cases being unexplained.
207
Not only
is the proportion of SCD that remains unexplained apparently
higher in the young but victims are more commonly young men
who die suddenly in their sleep or at rest.
203
Among predom-
inantly male U.S. military recruits aged 18 to 35 years old the
unexplained SCD rates is as high as 4.5/100,000 per annum,
accounting for 35% of all SCD in this group.
212
Aregional
Australian study of SCD in the 5 to 35 year old group confirms a
29% proportion as unexplained.
213
An autopsy series of the
general population in the Veneto region of Italy has, however,
suggested that normal hearts are present in only 6% of SCD
cases,
208
while a U.S. series of sudden deaths among athletes
found only a 3% prevalence.
214
Conversely, sudden deaths
among British athletes contained a 26% prevalence of morpho-
logically normal hearts.
215
There is therefore remarkable varia-
tion and discrepancy.
The incidence of unexplained sudden death below 1 year
of age (SIDS and SUDI) is well defined and exceeds the
incidence of SCD in young adults or in children over 1 year
of age by an order of magnitude. A recent national study
Heart Rhythm, Vol 0, No 0, Month 201318

from Ireland revealed a sudden death rate of 1.4/100,000
among children age 1–4 years compared to 59/100,000 in
those under 1 year.
216
A population based-study in the
United States revealed similar rates with an annual incidence
of SCD of 3/100,000 for children age 1–4 years and
80/100,000 for children o1 year.
217
It should be noted that
campaigns to avoid modifiable risk factors (predominantly
avoiding the prone sleeping position) have resulted in
significant declines in SIDS rates around the world. How-
ever, these have plateaued and the current rate of SIDS in the
United States is 53/100,000.
218
Diagnosis
The diagnosis of an unexplained SCD ideally relies upon an
autopsy and toxicological studies being undertaken to exclude
noncardiac etiologies. Further pathological evaluation of the
heart is then necessary with detailed histopathological exami-
nation to exclude clear causes for SCD.
219
This may identify
structural cardiac genetic disease such as hypertrophic cardio-
myopathy that would indicate the need for familial evaluation
and the retention of tissue suitable for DNA extraction and
targeted genetic testing. This examination is best undertaken
with the support of an expert cardiac pathologist to improve the
accuracy of diagnosis and guide familial evaluation.
210
In a
number of cases pathological findings may be equivocal as to
the cause of death: for example, idiopathic left ventricular
hypertrophy without histological disarray; bicuspid aortic valve;
or anomalous coronary artery without evidence for ischemia.
These should be considered unexplained as familial evaluation
can still uncover a significant burden of arrhythmia syndromes
in these cases.
220
If the death remains unexplained, then
additional investigations may prove helpful. Collection of any
available antemortem history or cardiac investigation may
provide clues but a normal antemortem ECG does not exclude
an underlying cardiac genetic cause, particularly when BrS has
been diagnosed in the family.
221
Retention of tissue suitable for
DNA extraction permits a molecular autopsy to either confirm a
genetic diagnosis or even make the diagnosis in up to 35% of
cases.
222
This may also prove helpful in the event of a SUDI
death as postmortem genetic testing reveals mutations in cardiac
channelopathy genes in an estimated 10% of SIDS cases.
222
Management
Once a diagnosis of SUDS has been made, further manage-
ment revolves around evaluating family members.
Screening of family members
When first-degree relatives of victims of SADS or premature
(less than 50 years old) unexplained sudden death undergo
cardiac assessment, up to half of families reveal cardiac genetic
diseases such as the arrhythmia syndromes (LQTS, BrS and
CPVT in particular) and occasionally subtle and difficult to
detect forms of cardiomyopathy (ARVC in particu-
lar).
202,209,223,224
If an autopsy has not been undertaken then
additional etiologies diagnosed in families include cardiomyo-
pathies in general and familial hypercholesterolemia.
209,223
The strategy for evaluation often is staged with less invasive
investigations first and then more invasive tests if a diagnosis is
not made (Figure 3). Family members who are more likely to be
affected include those with symptoms of concern such as
syncope or seizure, and obligate carriers.
224
The investigative
protocol may include personal history; family history and
history of sudden death victim; resting, exercise, signal-
averaged and ambulatory 24 hour ECG; echocardiography;
and provocation testing with sodium channel blocker and/or
epinephrine and cardiac MRI as required.
202,209,223,224
Signal-
averaged and ambulatory ECGs are least effective in making a
clinical diagnosis.
209,224
Resting and exercise ECG, Class I
drug challenge and cardiac imaging offer the most diagnostic
value consistently across studies.
209,224
A retrospective revision
of an autopsy diagnosis by an expert pathologist may also
support a diagnosis in a family.
209
The investigation of family members of cases of SUDI
deaths often occurs on an ad hoc basis yet there are little data
on its yield. Molecular autopsy identifies a lower burden of
ion channel disease in SIDS compared to SUDS and there is
a greater likelihood of sporadic genetic disease as a cause of
sudden death in infancy. It is therefore likely that the yield of
clinical evaluation of first-degree relatives will be signifi-
cantly lower than in SUDS. Nonetheless if there is a positive
molecular autopsy result, a family history of other cases of
SUDI, SUDS or premature unexplained sudden death or of
inherited heart disease then the yield is likely to be greater
and familial evaluation more worthwhile.
As with families of SUDS victims, it is reasonable that
relatives of SUDI deaths who are obligate carriers or have
ominous symptoms such as cardiac syncope should be
prioritized for evaluation. In families with SUDS deaths
young family members may require periodic reassessment
even if the initial assessment is normal as young patients may
only become cognizant of symptoms at an older age, and
certain diseases have age-related penetrance. Repeated
evaluations should occur if family members become symp-
tomatic or additional suspicious sudden deaths are identified
in the family.
10. Inherited Arrhythmia Clinics
Expert Consensus Recommendations on Inherited Arrhyth-
mia Clinic
Class I Patients (probands) and first-degree relatives with a
diagnosed or suspected inherited cardiovascular
disease as a potential cause of SCD (SUDS/
SUDI) should be evaluated in a dedicated clinic
with appropriately trained staff.
The evaluation and treatment of families suspected of
having inherited arrhythmias requires a multidisciplinary team
and approach. The presentation often is that of a proband or
family member who has experienced a life-threatening
arrhythmia, sudden cardiac arrest or SCD. In the usual
circumstance, there are profound and far-reaching medical
and psychosocial implications of both presentation of the
19Priori et al Expert Consensus Statement on Inherited Primary Arrhythmia Syndromes

Figure 3 Algorithm to describe the investigative strategy for identification of inherited heart disease in families that have suffered a SUDS event.
Heart Rhythm, Vol 0, No 0, Month 201320

inherited arrhythmia and genetic testing on patients and
families
1,2
The presence of an inherited arrhythmia or a
positive genetic test can dramatically change the life of a
patient and questions related to transmissibility of disease to
one’s children, participation in athletics, insurability and
prohibited types of employment are among the common
questions patients and families face. Perhaps the most
important role of the inherited arrhythmia clinic in the case
of the sudden death of a proband is to provide support, expert
evaluation, advice and treatment to surviving family members.
Recent evidence suggests that a structured inherited
arrhythmia (or inherited cardiovascular disease) clinic
improves the likelihood of making a diagnosis in suspected
cases of inherited arrhythmias and SCD.
196,209,224–227
The
promise of an appropriately resourced, structured clinic is
that of a comprehensive evaluation of patients and families,
more efficient use of diagnostic testing and therapy and ready
access to a broad range of medical, genetics and psychoso-
cial expertise in managing families afflicted by inherited
arrhythmias. An inherited cardiovascular disease clinic is an
invaluable resource to patients and families, not only at the
time of the initial evaluation but in an ongoing fashion as
medical, genetic and social questions relevant to the inher-
ited heart disease arise.
There are different operational models for inherited arrhyth-
mia clinics; the choice may be determined by the health system
or the regulations that exist in a given country. However, the
linchpins of a successful inherited heart disease clinic include
not only medical, nursing and genetics proficiency but a
dedicated staff with operational and logistic expertise who
have ready access to all team members. Each member of the
team has a key role to play in the optimal evaluation of families
suspected of having inherited arrhythmias. The personnel and
workflow in an ideal inherited arrhythmia clinic are illustrated
in the schematic in Figure 4. The key personnel include a clinic
coordinator who is responsible for patient intake, collection
and collation of medical records, scheduling appointments for
patients and family members and assisting with questions
relating to insurance coverage. The initial evaluation of
patients and family members may be performed by a nurse
specialist and genetics counselor.
228
This requires not only
review of medical records but also pedigree development,
collection and collation of medical testing such as imaging
studies, pathological specimens, autopsy reports and results of
previously performed genetic testing. In the ideal situation, the
results of testing on the patient or family members are
reviewed by the physicians, nurses and counselors prior to
the clinic visit. The physicians are typically a clinical
cardiologist/electrophysiologist with expertise in inherited
arrhythmias and medical genetics or a medical geneticist with
an interest in cardiac arrhythmias partnering with a clinical
electrophysiologist. In some countries, only a geneticist is
permitted to order and/or discuss genetic test results with
patients. It is important to bear in mind that many presenta-
tions that suggest an inherited arrhythmia may be the result of
acquired disease or an inherited cardiomyopathy. If the
inherited arrhythmia clinic is part of a larger program in
inherited heart disease, experts in cardiomyopathy will likely
be available; otherwise access to such experts is essential. The
team of physicians will perform the general medical evalua-
tion of the patient, review of the records, interpretation of test
results and development of diagnostic and identify the
Figure 4 Workflow and personnel in the evaluation of patients and families with inherited arrhythmias.
21Priori et al Expert Consensus Statement on Inherited Primary Arrhythmia Syndromes

treatment plans. In some cases evaluation of a family includes
postmortem review of a family member and the opinion of a
cardiac pathologist often is useful in making the proper
diagnosis.
The increasing complexity and demands of the proper
diagnosis and management of patients with inherited car-
diovascular disease create an opportunity for the develop-
ment of specialized training for clinical electrophysiologists
interested in the care of patients with inherited arrhyth-
mias.
229
Such a specialty track would consolidate aspects of
care involving indications and interpretation of genetic test
results and pharmacological and device therapy.
The management of patients with inherited arrhythmias
includes expert judgment regarding the indications, type and
interpretation of genetic testing. In collaboration with a
genetic counselor, patients and families should be properly
prepared regarding expectations and outcomes of genetic
testing. The role of genetic testing may vary depending upon
the exact inherited arrhythmia being considered, and the
particular mutation may have an impact on specific ther-
apeutic recommendations. Arguably the most important part
of the testing procedure is reviewing the test results and
implications with patient and family, being prepared to
discuss the implications for other family members, the
meaning of variants of uncertain significance (VUS), mosa-
icism and issues related to paternity and consanguinity. The
genetic counselor is an essential
228
and in some countries
legally mandated provider in this aspect of the care of
patients and families with suspected inherited arrhythmias.
The genetic test is only part of the management of a
patient with an inherited arrhythmia. The treatment of
patients with inherited arrhythmias may vary from medica-
tion therapy and lifestyle modification to device implantation
to LCSD. Patients may require invasive EPS and treatment
with pacemakers or ICDs. In some cases surgical or
thoracoscopic cardiac sympathetic denervation is required
for cardiac rhythm control and SCD prevention. In general
patients will require adjustment to both the underlying
disease and therapy, which could be assisted by access to
psychologists with an interest in patients with heart disease.
Patients in an inherited arrhythmia clinic may be survi-
vors of sudden cardiac arrest (SCA). The management of the
recovery of these patients from their index event may require
the expertise of psychologists and psychiatrists and the
intervention of physical and occupational therapists. More-
over, the diagnosis of an inherited disease of any kind,
particularly one that carries with it the risk of significant
morbidity and premature mortality, is often associated with
significant emotional distress that at times will require
referral of patients and families.
230–236
A structured inherited arrhythmia (or heart disease) clinic
provides the platform for optimized, multidisciplinary evalua-
tion and management of patients and families with suspected
inherited heart disease. The collective efforts of the core staff
and access to a variety of experts in related disciplines will
result in improved quality of care,
224,226,233,237–242
patient
satisfaction,
233
and improvement in appropriate use of
diagnostic testing
196,209
and therapeutic intervention. The
promise of such a clinic structure is lower overall cost and
improvement in patient outcomes.
Appendix A
See Tables A1 and A2
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27Priori et al Expert Consensus Statement on Inherited Primary Arrhythmia Syndromes

Table A1 Writing group author disclosure table
Writing group Employment
Consultant/
advisory board
Speakers'bureau/
honoraria Research grant Fellowship support
Board Mbs/stock
options/partner Others
Nico Blom, MD, PhD Academical Medical Center,
Amsterdam, Leiden
University Medical
Center, Leiden,
Netherlands
None None None None None None
Elijah R. Behr,
MA, MBBS,
MD, FRCP
Cardiovascular Sciences
Research Centre, St.
Georges University of
London, London, UNITED
KINGDOM
None None Biotronik British Heart Foundation (f)
Boston Scientific-shared
with colleague (f) St.
Jude Medical-shared with
colleague (f) Cardiac Risk
in the Young (f)
None EU-FP7 research project (f)
St. Jude Medical-
consumables for research
(b) British Heart
Foundation-Research
Grants (f)
Charles I. Berul,
MD, FHRS, CCDS
Children's National Medical
Center, Washington, DC,
USA
Johnson and Johnson (c)
Pierre-Fabre Pharm
(DSMB) (c)
None None None None None
Josep Brugada,
MD, PhD
Thorax Institute, Hospital
Clinic, University of
Barcelona, SPAIN
Sorin (b) None None None None None
Chern-En Chiang,
MD, PhD
Taipei Veteran's General
Hospital and National
Yang Ming University,
Taipei, TAIWAN
Astrazeneca (b); Bayer (b);
Boehringer Ingelheim
(b); Daichi-Sankyo (b);
Novartis (b)
Astrazeneca (b); Bayer (b);
Boehringer Ingelheim
(b); Daichi-Sankyo (b);
Merck Sharp & Dohme
(b);Novartis (b);Pfizer
(b); Sanofi(b); Roche
(b); Servier (b);Tanabe
(b);Takeda (b)
None None None None
Yongkeun Cho,
MD, PhD
Kyungpook National
University Hospital,
Taegu, SOUTH KOREA
None None None None None None
Minoru Horie,
MD, PhD
Shiga University of Medical
Sciences, Department of
Cardiology, Otsu, JAPAN
Daiichi-sankyo (b)
Sanofi-Aventis (b)
Boelinger Japan (b)
Takeda Pharma (b)
None None None None None
Heikki Huikuri,
MD
Oulu University Central
Hospital, Division of
Cardiology Medicine,
Oulu, FINLAND
SanofiWinthrop (b)
Bohringer Ingelheim (b)
Bayer (b) Merck (b)
None Daiichi Sankyo
Pharma Dev. (d)
None None None
Prince Kannnankeril, MD,
HRS
Vanderbilt Children's
Hospital, Division of
None None NIH (f) None None None
Heart Rhythm, Vol 0, No 0, Month 201328

Table A1 (continued )
Writing group Employment
Consultant/
advisory board
Speakers'bureau/
honoraria Research grant Fellowship support
Board Mbs/stock
options/partner Others
Pediatric Cardiology,
Nashville, Tennessee
Andrew D. Krahn,
MD, FHRS
University of Western
Ontario, University
Hospital, London,
CANADA
Medtronic (b) None Medtronic (f) St Jude
Medical (f) Boston
Scientific (f)
Medtronic (d)
St Jude Medical (c)
None None
Antoine Leenhardt, MD AP-HP, Bichat Hospital,
Service de Cardiologie et
Centre de Référence des
Maladies Cardiaques
Héréditaires, Paris,
France
Servier (b); Sanofi(b);
MEDA Pharma (b); Bayer
(b);St. Jude Medical (b);
MSD (b); Boston
Scientific (b); Medtronic
(b); Biotronik (b);
Boehringer Ingelheim (b)
Genzyme (b)
None None None None None
Arthur J. Moss,
MD, HRS
University Rochester
Medical Center,
Rochester, NY, USA
Boston Scientific (b);
Medtronic (b); St. Jude
(b); Biotronic (b)
None Boston Scientific (f)
BioReference Labs
(f) NIH (f)
None None None
Silvia G. Priori,
MD, PhD, HRS
Maugeri Foundation IRCCS,
Pavia, Italy, Department
of Molecular Medicine,
University of Pavia,
Pavia, Italy and New York
University, New York,
New York
Medtronic (b); Boston
Scientific (b); Biotronic
(b); Transgenomic (b)
None None None None None
Peter J. Schwartz,
MD, HRS
University of Pavia,
Department of Molecular
Medicine, Pavia, ITALY
BioControl Medical Ltd (b)
St. Jude Medical (b)
Institut de Recherches
Internationales
Servier (b)
Institut de Recherches
Internationales Servier
(b)
Institut de
Recherches
Internationales
Servier (b)
None None None
Wataru Shimizu,
MD, PhD, HRS
Nippon Medical School,
Tokyo, Japan
Boelinger Japan (b); Sanofi-
Aventis (b);itsubishi
Japan (b); Daiichi-sankyo
(b); Bayer Japan (b);
Bristol-Myers Squibb
(b); Medtronic (b);
Biotronic (b)
None None None None None
Gordon Tomaselli,
MD, FHRS
Johns Hopkins Unviersity,
Baltimore, MD, USA
None None None None American Heart
Association (a)
None
29Priori et al Expert Consensus Statement on Inherited Primary Arrhythmia Syndromes

Table A1 (continued )
Writing group Employment
Consultant/
advisory board
Speakers'bureau/
honoraria Research grant Fellowship support
Board Mbs/stock
options/partner Others
Cynthia Tracy,
MD, HRS
George Washington
University Medical
Center, Department of
Cardiology, Washington,
DC, USA
None None None None None None
Arthur A Wilde,
MD, PhD, HRS
University of Amsterdam -
Academic Medical Center,
Amsterdam,
NETHERLANDS
Sorin (b) None None None None None
Number Value: (a) ¼$0; (b) ¼o$10,000; (c) ¼4$10,000 to o$25,000; (d) ¼4$25,000 to o$50,000; (e) ¼4$50,000 to o$100,000; (f) ¼4$100,000.
Heart Rhythm, Vol 0, No 0, Month 201330

Table A2 Peer reviewer disclosure table
Peer review Employment
Consultant/
advisory board
Speakers'bureau/
honoraria Research grant Fellowship support
Board Mbs/stock
options/partner Others
Michael Ackerman,
MD, PhD
Mayo Clinic College of
Medicine, Rochester,
MN, USA
1; Biotronik, Boston
Scientific Corp.,
Medtronic Inc.,
St. Jude Medical
None 5; National
Institutes of
Health
None None Royalties-4;
Transgenomic
Bernard Belhassen,
MD
Tel Aviv Medical Center,
Tel Aviv, ISRAEL
None None None None None None
N. A. Mark Estes III,
MD, FHRS
New England Medical
Center, Boston, MA,
USA
1; Medtronic Inc.
2; Boston Scientific
Corp.
None 4: Boston Scientific
Corp.
4; Medtronic Inc.,
Boston Scientific
Corp., St. Jude
Medical
None None
Diane Fatkin, MD Victor Change Cardiac
Research Institute,
Darlinghurst,
AUSTRALIA
None None 5; NHMRC Senior
Research
Fellowship
None None Salary- 4; Victor Chang
Cardiac Research
Institute, partial
salary support
Jonathan Kalman,
PhD, FHRS
Royal Melbourne
Hospital, Melbourne,
AUSTRALIA
None None 4; Medtronic, Inc. 3; St. Jude Medical
4; Medtronic Inc.
None None
Elizabeth Kaufman,
MD, FHRS
Metrohealth Medical
Center, Cleveland,
OH, USA
1; St. Jude Medical None 2; Cambridge Heart,
Inc.
None None None
Paulus Kirchhof, MD University Hospital
Muenster
1; 3M Medica, Bayer
Healthcare LLC,
Bristol Meyers
Squibb, Eli Lilly,
Boehringer
Ingelheim, Daiichi,
Medtronic Inc.,
SanofiAventis, St.
Jude Medical, Merck
Parmaceuticals
None 5; SanofiAventis,
St. Jude Medical,
3M Medica,
German Ministry
of Education and
Research (BMBF)
None None None
Eric Schulze-Bahr,
MD, PhD
University of Munster,
Munster, GERMANY
None None None None None None
Christian Wolpert,
MD
University Hospital
Mannheim,
Ludwigsburg,
GERMANY
1; Medtronic Inc., St.
Jude Medical, Bard
Electrophysiology,
Sorin Group
None None None None None
31Priori et al Expert Consensus Statement on Inherited Primary Arrhythmia Syndromes

Table A2 (continued )
Peer review Employment
Consultant/
advisory board
Speakers'bureau/
honoraria Research grant Fellowship support
Board Mbs/stock
options/partner Others
Jitendra Vohra,
MD
Royal Melbourne
Hospital, Melbourne,
AUSTRALIA
None None None None None None
Marwan Refaat,
MD
Univeristy of California,
San Francisco, CA,
USA
None None None None None None
Susan P. Etheridge,
MD, FHRS
University of Utah, Salt
Lake City, UT, USA
None None None None None None
Robert M. Campbell,
MD
Sibley Heart Center,
Emory University
School of Medicine,
Atlanta, GA, USA
None None None None None None
Edward T. Martin,
MD
Oklahoma Heart
Institute, Tulsa, OK,
USA
1; Lantheus, Siemens, None None None None None
Swee Chye Quek,
MD
National Univeristy of
Singapore,
SINGAPORE
None None None None None None
Number Value: 0 ¼$0; 1 ¼r$10,000; 2 ¼4$10,001 to r$25,000; 3 ¼4$25,001 to r$50,000; 4 ¼4$50,001 to r100,000; 5 ¼4$100,001.
Heart Rhythm, Vol 0, No 0, Month 201332