Accepted Manuscript Title: Update on the Diagnosis and Management of Brugada Syndrome Author: Jitendra Vohra Sulekha Rajagopalan PII: DOI: Reference:
S1443-9506(15)01330-X http://dx.doi.org/doi:10.1016/j.hlc.2015.07.020 HLC 1945
To appear in: Received date: Accepted date:
23-7-2015 23-7-2015
Please cite this article as: Vohra J, Rajagopalan S, on behalf of the CSANZ Genetics Council Writing Group, Update on the Diagnosis and Management of Brugada Syndrome, Heart, Lung and Circulation (2015), http://dx.doi.org/10.1016/j.hlc.2015.07.020 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Brugada CSANZ update
Page | 1
1
Update on the Diagnosis and Management of
2
Brugada Syndrome Jitendra Vohra, MD, FRACP, FCSANZ, 2Sulekha Rajagopalan FRACP; on behalf of the
5
1
Cardiology Department, The Royal Melbourne Hospital and Department of Medicine University of Melbourne, Melbourne
6 2
Department of Clinical Genetics, Liverpool Hospital, Liverpool
an
7
Corresponding Author: Professor Jitendra Vohra, MD, FRACP, FCSANZ Cardiology Department The Royal Melbourne Hospital and Department of Medicine, University of Melbourne RMH, Victoria 3050 Australia Phone: +61 3 8387 2000 Fax: +61 3 8387 2222 Email: [email protected]
19
Keywords:
20
Syncope; Heart disease
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8 9 10 11 12 13 14 15 16 17 18
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cr
CSANZ Genetics Council Writing Group
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ip t
1
us
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Brugada Syndrome; Atrial fibrillation; Genetic testing; Sudden death;
Page 1 of 28
Brugada CSANZ update
Page | 2
Abstract
23
Brugada Syndrome (BrS) is an autosomal dominant channelopathy with variable penetrance
24
affecting the sodium channel. It reduces the transport of sodium ions essential for proper
25
generation of the cardiac action potential. The resulting inhomogeneous repolarisation in
26
areas of the RV epicardium causes malignant ventricular arrhythmias.
27
BrS is diagnosed by typical cove shaped ST elevation of > 2mm in ≥1 RV precordial lead V1,
28
V2 occurring spontaneously or after provocative drug test with IV administration of Class 1
29
antiarrhythmic drug such as flecainide or ajmaline.
30
The incidence of BrS is variable being higher in South East Asians and is generally quoted as
31
1,2000. It is responsible for up to 20% of sudden arrhythmic deaths in those without
32
structural heart disease. Typical presentation is syncope or resuscitated sudden death and
33
symptoms usually occur at night or at rest especially after a large meal. Fever is a common
34
trigger, particularly in children.
35
Genetic testing for BrS is a Class 2A indication and the yield has increased recently to nearly
36
40%. Genetic testing assists with family screening.
37
Management of Brugada Syndrome
38
Resuscitated cardiac arrest and cardiac syncope are Class 1 indications for implantation of an
39
ICD. All family members of BrS patients should be screened and those with normal or non-
40
diagnostic ECGs should be offered ajmaline or flecainide test. ICD implantation in BrS has a
41
significant complication rate and should be avoided in asymptomatic patients. Family history
42
of sudden death is not an indication for ICD implantation. Asymptomatic patients should be
43
advised of lifestyle measures such as avoidance of ‘Brugada drugs’, prompt treatment of
44
fever and avoiding excess of alcohol and big carbohydrate meals at night.
Ac ce p
te
d
M
an
us
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22
Page 2 of 28
Brugada CSANZ update
Page | 3
Risk Assessment of Asymptomatic Brugada Syndrome Patients
46
Event rate in those with spontaneous type 1 ECG has been reported as 0.24 to 1.7% per year.
47
Drug induced BrS pattern ECG patients are at minimal risk. Several major trials have
48
reported that programmed electrical stimulation is not helpful in risk stratification.
49
Fragmentation of QRS on the ECG, RV ERP of ≤200msec, history of syncope, atrial
50
fibrillation and spontaneous type 1 Brugada pattern on the ECG, put the patient in the higher
51
risk category.
52
Treatment of Arrhythmic Storms
53
Isoprenaline infusion is effective in acute situations and quinidine is the only effective drug in
54
long-term treatment.
an
us
cr
ip t
45
Ac ce p
te
d
M
55
Page 3 of 28
Brugada CSANZ update
Page | 4
1
Clinical Characteristics
57
1.1
Definition and prevalence
58
Brugada Syndrome (BrS) was described as a clinical entity in 1992. (1) The diagnosis is
59
made by electrocardiogram (ECG) and is defined by the presence of an atypical right bundle
60
branch block (RBBB) pattern with a characteristic cove-shaped ST elevation in leads V1 to
61
V3, in the absence of obvious structural heart disease, electrolyte disturbances or ischaemia.
62
Inheritance can be autosomal dominant with incomplete penetrance, or be polygenic.(2, 3) It
63
can also appear as a consequence of structural changes in the right ventricular outflow tract
64
from a variety of causes. BrS is reported to be responsible for 4% of all sudden deaths and
65
20% of sudden deaths in those without structural heart disease and is a leading cause of death
66
in subjects under the age of 40 years. A family history is present in about 20 to 30% of
67
patients. It is difficult to estimate the exact incidence of BrS in the general population but the
68
prevalence is quoted as 1 in 2000. (4-6) The condition is particularly common in South East
69
Asia and amongst migrants of South Asian origin and in the Japanese population the
70
prevalence is reported to be 0.5-1 per 1000. BrS has also been reported as Sudden
71
Unexplained Death Syndrome (SUDS) or Sudden Unexplained Nocturnal Death Syndrome
72
(SUNDS).(7) The ECG changes of BrS are dynamic and can vary spontaneously.
73
BrS appears to be a channelopathy, which, besides electrophysiological changes, there have
74
also been reports of subtle structural changes in the atria and the right ventricular outflow
75
tract (RVOT). (4)
76
1.2
77
The most typical presentation is syncope or resuscitated sudden death in the third or fourth
78
decade of life due to polymorphic ventricular tachycardia (VT) or ventricular fibrillation
79
(VF). Symptoms typically occur at night, or at rest during the day but also uncommonly
Ac ce p
te
d
M
an
us
cr
ip t
56
Clinical presentation
Page 4 of 28
Brugada CSANZ update
Page | 5
during exercise.(2) Monomorphic VT is rare and is more prevalent in children and infants,
81
among whom fever is the commonest trigger.(8, 9) The diagnosis of BrS may also be made
82
on family screening of patients with BrS or incidentally following a routine ECG. More than
83
80% of adult patients are males but in children there is an equal male:female ratio. Many
84
subjects remain asymptomatic throughout life.
85
1.3
86
Consensus statements regarding making the diagnosis of Brugada Syndrome
87
The first consensus report of 2002 proposed using ECG criteria alone. These are shown in
88
Figure 1. Three subtypes of ECG features have been recognised. (3)
89
i) Type 1: Cove-shaped ST elevation in right precordial leads with J wave or ST elevation of
90
≥ 2mm (mV) at its peak followed by a negative T wave with little or no isoelectric interval in
91
more than one right precordial leads V1-V3.
92
ii) Type 2: The ST segments also have a high take-off but the J amplitude of ≥ 2mV gives rise
93
to a gradually descending ST elevation remaining ≥ 1mV above the baseline followed by a
94
positive or biphasic T wave that results in a saddle back configuration.
95
iii) Type 3: Right precordial ST elevation of
S1443-9506(15)01330-X http://dx.doi.org/doi:10.1016/j.hlc.2015.07.020 HLC 1945
To appear in: Received date: Accepted date:
23-7-2015 23-7-2015
Please cite this article as: Vohra J, Rajagopalan S, on behalf of the CSANZ Genetics Council Writing Group, Update on the Diagnosis and Management of Brugada Syndrome, Heart, Lung and Circulation (2015), http://dx.doi.org/10.1016/j.hlc.2015.07.020 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Brugada CSANZ update
Page | 1
1
Update on the Diagnosis and Management of
2
Brugada Syndrome Jitendra Vohra, MD, FRACP, FCSANZ, 2Sulekha Rajagopalan FRACP; on behalf of the
5
1
Cardiology Department, The Royal Melbourne Hospital and Department of Medicine University of Melbourne, Melbourne
6 2
Department of Clinical Genetics, Liverpool Hospital, Liverpool
an
7
Corresponding Author: Professor Jitendra Vohra, MD, FRACP, FCSANZ Cardiology Department The Royal Melbourne Hospital and Department of Medicine, University of Melbourne RMH, Victoria 3050 Australia Phone: +61 3 8387 2000 Fax: +61 3 8387 2222 Email: [email protected]
19
Keywords:
20
Syncope; Heart disease
Ac ce p
te
d
M
8 9 10 11 12 13 14 15 16 17 18
21
cr
CSANZ Genetics Council Writing Group
4
ip t
1
us
3
Brugada Syndrome; Atrial fibrillation; Genetic testing; Sudden death;
Page 1 of 28
Brugada CSANZ update
Page | 2
Abstract
23
Brugada Syndrome (BrS) is an autosomal dominant channelopathy with variable penetrance
24
affecting the sodium channel. It reduces the transport of sodium ions essential for proper
25
generation of the cardiac action potential. The resulting inhomogeneous repolarisation in
26
areas of the RV epicardium causes malignant ventricular arrhythmias.
27
BrS is diagnosed by typical cove shaped ST elevation of > 2mm in ≥1 RV precordial lead V1,
28
V2 occurring spontaneously or after provocative drug test with IV administration of Class 1
29
antiarrhythmic drug such as flecainide or ajmaline.
30
The incidence of BrS is variable being higher in South East Asians and is generally quoted as
31
1,2000. It is responsible for up to 20% of sudden arrhythmic deaths in those without
32
structural heart disease. Typical presentation is syncope or resuscitated sudden death and
33
symptoms usually occur at night or at rest especially after a large meal. Fever is a common
34
trigger, particularly in children.
35
Genetic testing for BrS is a Class 2A indication and the yield has increased recently to nearly
36
40%. Genetic testing assists with family screening.
37
Management of Brugada Syndrome
38
Resuscitated cardiac arrest and cardiac syncope are Class 1 indications for implantation of an
39
ICD. All family members of BrS patients should be screened and those with normal or non-
40
diagnostic ECGs should be offered ajmaline or flecainide test. ICD implantation in BrS has a
41
significant complication rate and should be avoided in asymptomatic patients. Family history
42
of sudden death is not an indication for ICD implantation. Asymptomatic patients should be
43
advised of lifestyle measures such as avoidance of ‘Brugada drugs’, prompt treatment of
44
fever and avoiding excess of alcohol and big carbohydrate meals at night.
Ac ce p
te
d
M
an
us
cr
ip t
22
Page 2 of 28
Brugada CSANZ update
Page | 3
Risk Assessment of Asymptomatic Brugada Syndrome Patients
46
Event rate in those with spontaneous type 1 ECG has been reported as 0.24 to 1.7% per year.
47
Drug induced BrS pattern ECG patients are at minimal risk. Several major trials have
48
reported that programmed electrical stimulation is not helpful in risk stratification.
49
Fragmentation of QRS on the ECG, RV ERP of ≤200msec, history of syncope, atrial
50
fibrillation and spontaneous type 1 Brugada pattern on the ECG, put the patient in the higher
51
risk category.
52
Treatment of Arrhythmic Storms
53
Isoprenaline infusion is effective in acute situations and quinidine is the only effective drug in
54
long-term treatment.
an
us
cr
ip t
45
Ac ce p
te
d
M
55
Page 3 of 28
Brugada CSANZ update
Page | 4
1
Clinical Characteristics
57
1.1
Definition and prevalence
58
Brugada Syndrome (BrS) was described as a clinical entity in 1992. (1) The diagnosis is
59
made by electrocardiogram (ECG) and is defined by the presence of an atypical right bundle
60
branch block (RBBB) pattern with a characteristic cove-shaped ST elevation in leads V1 to
61
V3, in the absence of obvious structural heart disease, electrolyte disturbances or ischaemia.
62
Inheritance can be autosomal dominant with incomplete penetrance, or be polygenic.(2, 3) It
63
can also appear as a consequence of structural changes in the right ventricular outflow tract
64
from a variety of causes. BrS is reported to be responsible for 4% of all sudden deaths and
65
20% of sudden deaths in those without structural heart disease and is a leading cause of death
66
in subjects under the age of 40 years. A family history is present in about 20 to 30% of
67
patients. It is difficult to estimate the exact incidence of BrS in the general population but the
68
prevalence is quoted as 1 in 2000. (4-6) The condition is particularly common in South East
69
Asia and amongst migrants of South Asian origin and in the Japanese population the
70
prevalence is reported to be 0.5-1 per 1000. BrS has also been reported as Sudden
71
Unexplained Death Syndrome (SUDS) or Sudden Unexplained Nocturnal Death Syndrome
72
(SUNDS).(7) The ECG changes of BrS are dynamic and can vary spontaneously.
73
BrS appears to be a channelopathy, which, besides electrophysiological changes, there have
74
also been reports of subtle structural changes in the atria and the right ventricular outflow
75
tract (RVOT). (4)
76
1.2
77
The most typical presentation is syncope or resuscitated sudden death in the third or fourth
78
decade of life due to polymorphic ventricular tachycardia (VT) or ventricular fibrillation
79
(VF). Symptoms typically occur at night, or at rest during the day but also uncommonly
Ac ce p
te
d
M
an
us
cr
ip t
56
Clinical presentation
Page 4 of 28
Brugada CSANZ update
Page | 5
during exercise.(2) Monomorphic VT is rare and is more prevalent in children and infants,
81
among whom fever is the commonest trigger.(8, 9) The diagnosis of BrS may also be made
82
on family screening of patients with BrS or incidentally following a routine ECG. More than
83
80% of adult patients are males but in children there is an equal male:female ratio. Many
84
subjects remain asymptomatic throughout life.
85
1.3
86
Consensus statements regarding making the diagnosis of Brugada Syndrome
87
The first consensus report of 2002 proposed using ECG criteria alone. These are shown in
88
Figure 1. Three subtypes of ECG features have been recognised. (3)
89
i) Type 1: Cove-shaped ST elevation in right precordial leads with J wave or ST elevation of
90
≥ 2mm (mV) at its peak followed by a negative T wave with little or no isoelectric interval in
91
more than one right precordial leads V1-V3.
92
ii) Type 2: The ST segments also have a high take-off but the J amplitude of ≥ 2mV gives rise
93
to a gradually descending ST elevation remaining ≥ 1mV above the baseline followed by a
94
positive or biphasic T wave that results in a saddle back configuration.
95
iii) Type 3: Right precordial ST elevation of
