Transcript Brugada - Department of Medicine

Academy of Medicine
Case presentation
Travis Nesbit
7/10/2015
History of Present Illness
• 35 yr M BIB ambulance after cardiac arrest while sleeping.
Patient awoke from sleep with a scream and groan. Began
agonal breathing, cyanotic skin color developed.
• Partner began rescue-breathing, no CPR. It was 6-8 minutes
until EMS; 11 minutes after initial event.
• EMS identified ventricular fibrillation. AED x 8 rounds of
defibrillation and epi x 2.
• ROSC achieved and patient was intubated.
• During transport wide-complex tachycardia @ 140 bpm; EMS
started lidocaine.
2
Department Name | Month X, 201X
Pertinent History
• Past Medical History
• Schizophrenia
• Medications
• divalproex sodium 1,000 mg daily
• Family History
• No family history of heart disease
• No family history of sudden cardiac events or death
• Social History
• No tobacco
• Social light alcohol
• No illicit drugs
3
Department Name | Month X, 201X
Physical Exam
Vitals: BP 110/60 mmHg, HR 75 bpm, O2 100% on 1.0 FiO2
•
Head/neck: intubated, NC/AT
•
Cardiovascular: RRR, no M/R/G, no JVD, no bruits
•
Pulmonary: CTA bilaterally
•
Abdominal: soft, NT/ND
•
Extremities: peripheral pulses present and “normal”, +BS
•
Genitourinary: guaiac negative stool
•
Neurological: GCS of 5-T, PERRL 4->2mm, not following commands, not tracking, no
corneal reflex, symmetric face, tone increased in arms, legs rigid, spontaneously
moving extremities, withdraws to noxious stimuli in arms but not legs, toes turned
down.
4
Department Name | Month X, 201X
Diagnostic Data
• CT Head: diffuse cerebral edema with loss or blurring of the
junction of the gray matter with white matter.
• CBC: unremarkable
• CMP: unremarkable
• Magnesium: normal
• Phosphorus: normal
• CKMB: normal
• Troponin: normal
• Urine Tox: unremarkable
5
Department Name | Month X, 201X
Diagnostic Data
ECG
Right-sided ECG
6
Department Name | Month X, 201X
Summary
This is a 35 year old male/female with ventricular fibrillationinduced arrest.
What is the next best step?
7
Department Name | Month X, 201X
Differential Diagnosis – Brace yourself =)
• Non-cardiac causes of ventricular fibrillation
• Respiratory
•
•
•
•
•
Bronchospasm
Aspiration
Sleep apnea
Primary pulmonary hypertension
Pulmonary embolism
• Metabolic / toxic
•
•
•
•
8
Electrolyte disturbances
Medications or drug ingestion
Environmental poisoning
Sepsis
Department Name | Month X, 201X
Differential Diagnosis
• Non-cardiac causes of ventricular fibrillation continued.
• Neurologic
•
•
Seizure
Cerebrovascular accidental
•
Intracranial hemorrhage
•
Ischemic stroke
• Cardiac causes of ventricular fibrillation
• Structural heart disease
•
•
•
9
Myocardial ischemia
Myocardial infarction
Cardiomyopathy
•
Dilated
•
Hypertrophic
•
Arrythmogenic right ventricular cardiomyopathy or dysplasia
Department Name | Month X, 201X
Differential Diagnosis
• Cardiac causes of ventricular fibrillation continued.
• Structural heart disease continued
•
•
•
•
•
Aortic stenosis
Aortic dissection
Pericardial tamponade
Congenital heart disease
Myocarditis
• No structural heart disease
•
•
•
•
•
•
•
Catecholaminergic polymorphic ventricular tachycardia
Right ventricular outflow tract tachycardia
Mechanical accidents
Electrical accidents
Preexcitation
Heart block
Drug-induced QT prolongation with torsades de pointes
10 Department Name | Month X, 201X
Differential Diagnosis
• Cardiac causes of ventricular fibrillation continued.
• No structural heart disease
• Channelopathies
•
•
•
Long-QT syndrome
Short-QT syndrome
Brugada syndrome
11 Department Name | Month X, 201X
Patient’s Course
• Cardiology consulted
• Patient had cardiac catheterization
• Normal coronary arteries
• 50% ejection fraction
• Patient was transferred to CCU
• Opted against AICD while clinically unstable
• Opted against hypothermia protocol as patient had purposeful
movements and was not comatose
• Cooling blanket + acetaminophen to maintain euthermic state
• Additional Imaging Obtained
12 Department Name | Month X, 201X
Patient’s Course
Repeat ECG Obtained same day.
13 Department Name | Month X, 201X
Patient’s Course
• MRI showed anoxic brain injury (not patient’s image)
14 Department Name | Month X, 201X
Patient’s Course
• HD #2 patient had bloody BM.
• CT scan abdomen / pelvis: ischemic colitis
(Not patients imaging)
15 Department Name | Month X, 201X
Patient’s Course
Changes on repeat ECG at 31 hours.
16 Department Name | Month X, 201X
Patient’s Course
• HD #3 patient comatose
• Neurology provided very poor prognosis
• Transitioned to comfort measures only
• No autopsy performed
17 Department Name | Month X, 201X
Diagnosis?
18 Department Name | Month X, 201X
Pathophysiology
• Diagnosis: The Brugada Syndrome
• Autosomal dominant mutation of sodium channel
• No structural heart disease
• Premature inactivation and other loss-of-function abnormalities
• Na channel mutation is only known cause; 1/3rd of cases
• Genetic testing available, but low sensitivity and negative results not
useful
• In this patient sodium channel SCN5A was analyzed and found to be
normal
• Conducting defect within and between the ventricular epicardium and
endocardium 
•
•
heterogeneous cellular repolarization across the myocardium
potential for reentrant ventricular tachydysrhythmias 
•
polymorphic ventricular tachycardia
•
ventricular fibrillation
19 Department Name | Month X, 201X
Pathophysiology
Purple = Brugada
mutations
20 Department Name | Month X, 201X
Diagnosis
1. Appearance of a Type-1 (next slide) ST-segment elevation in
more than one lead (V1-V3)
• In absence or presence of sodium channel blocking agent
2. Plus one of the following:
• Documented ventricular fibrillation
• Polymorphic ventricular tachycardia
• Family history of sudden death in age < 45 years
• Inducibility of ventricular arrhythmias
• Presence of a coved-type ECG in family members
• Syncope
• Nocturnal agonal respiration
21 Department Name | Month X, 201X
Types
Type 1
Type 2 (non-diag)
Type 3 (non-diag)
J-Point
>= 2 mm
>= 2 mm
>= 2mm
T-wave
Negative
Positive or biphasic
Positive
ST-T configuration
Coved type
Saddleback
Saddleback
ST segment
(terminal portion)
Gradually
descending
Elevated >= 1 mm
Elevated < 1 mm
22 Department Name | Month X, 201X
Diagnosis
23 Department Name | Month X, 201X
Epidemiology
• Prevalent in Southeast Asian population
• Incidence of 5 of 10,000
• Clinical manifestations 9x more common in men than women
• Symptoms often first occur in third of fourth decade of life at
rest or during sleep
24 Department Name | Month X, 201X
Clinical Features
• History of syncope
• Inducible polymorphic ventricular tachycardia or fibrillation
• Sudden death may be first and only event
• Common at night when sleeping
• Polymorphic VT or VF in 17-42% of diagnosed patients
• Syncope, neutrally mediated
• ECG features decrease w/ exercise and sympathetic stimulation
• ECG features increase w/ temperature and Class I
antidysrythmic agents (e.g. flecainide, or procainamide).
25 Department Name | Month X, 201X
Treatment Options
• Focused around terminating ventricular arrhythmias
• AICD is first line therapy
• If recurrent shocks or patient refuses AICD, can consider adding
anti-arrythmics
• Amiodarone
• Quinidine
• RCCT of 63 patients with BS over three years
• 0% mortality with ICD
• 26% mortality with pharmacologic
• 32% mortality with no treatment
26 Department Name | Month X, 201X
Brugada Syndrome
Additional slides provided by Dr. Mitiku
Brugada Syndrome
Objectives
• General Characteristics
• Diagnostic Criteria and Genetics
• Clinical Manifestations
• Diagnostics Tools and Risk Stratification
• Treatment Options
• Interesting recent developments
28
General Characteristics
Dysfunction of a cardiac channel participating in the action
potential favoring arrhythmias initially described in 1992
No concomitant “structural heart disease”
Incidence 5 of 10,000
Majority of affected individuals are Asian
So-called sudden unexplained death syndrome (SUDS), today
known to be phenotypically, genetically, and functionally the
same disorder as the Brugada syndrome
29
Prevalence
In Thailand, estimated to be the second leading cause of death in
men <40, after accidents.
In the Philippines, known as Bangungut- scream followed by
sudden death during sleep
Japan as Pokkuri- unexpected sudden death at night.
• 0.12 to 0.16 percent of the Japanese population have type 1
(coved type) ST segment elevation
United States, the prevalence is 0.012- 0.4 percent
30
Description of the syndrome
A clinical and electrocardiographic syndrome
No demonstrable “structural heart disease”
Suffering from cardiac arrhythmias
31
Genetics (Briefly)
Autosomal dominant mode of transmission, but can be
sporadic
SCN5A, the gene encoding the αlpha subunit of the
cardiac sodium channel
• described by Chen in 1998
• quantitative decrease and qualitative dysfunction
• currently found in only 18% to 30% of patients with Brugada
syndrome, suggesting genetic heterogeneity
– Meaning different locus on chromosome 3 not linked to SCN5A
32
Genetics (Briefly)
Glycerol-3-phosphate dehydrogenase 1–like (GPD-1L), which
seems to affect the trafficking of the cardiac sodium channel to
the cell surface
Resulting mutation reduces sodium current by approximately 50%
33
Additional Loci
Cardiac calcium channel gene — In a series of 82 probands with a
clinical diagnosis of BS,
• seven individuals (8.5 percent) were found to have mutations
in the alpha1 or beta2 subunit of the cardiac L-type calcium
channel.
Three of these patients had a unique phenotype in that in
association with the typical ECG findings of BS, they also had
shortened QT intervals (≤360 msec).
The relationship of this disorder to the usual form of BS and to
short QT syndrome remains to be defined.
34
Genetic- new genes are being discovered every year
SCN5A alpha subunit of the sodium channel.
• Gain of this channel leads to an unopposed Ito current
GPD1L Glycerol-3-phosphate dehydrogenase like peptide
CACNA1C Alpha subunit of cardiac L-type calcium channel
CACNB2 Beta-2 subunit of the voltage dependent L-type calcium channel
KCNE3 which coassembles with KCND3 Beta subunit to KCND3. Modulates the
Ito potassium outward current
SCN1B Beta-1 subunit of the sodium channel SCN5A
35
Pathogenesis
A variety of factors may contribute to BS
• Right ventricular abnormalities,
• mutations in the cardiac sodium channel gene SCN5A etc
• autonomic tone
• Other factors
The BS demonstrates autosomal dominant inheritance-SCN5A
• Variable expression
• Variable Penetrance/compound heterozygosity
Mutations in SCN5A
• Found in 18 to 30% of families with BS
• The gene locus is on chromosome 3p21-24
36
Structural abnormalities
NO apparent structural heart disease.
Standard cardiac testing, including echocardiography, stress
testing, and cardiac magnetic resonance imaging often reveal no
abnormalities.
It is probably more accurate to categorize BS as a disorder that
occurs in hearts that are apparently normal
• There is some evidence that subtle structural or microscopic abnormalities
occur,
• including dilation of the RVOT and localized inflammation and fibrosis
37
Structural abnormalities
Mouse model of heterozygous SCN5A knockout revealed agedependent fibrosis and marked slowing of conduction velocity in
the right ventricle
Further evidence of microscopic abnormalities in BS comes from a
series of 18 patients who underwent endomyocardial biopsy
38
Figure 7. Histology.
Coronel R et al. Circulation 2005;112:2769-2777
Copyright © American Heart Association
Figure 1. Baseline ECG (A) from patient 7 showing ST-segment elevation in the right
precordial leads consistent with type I Brugada pattern.
Frustaci A et al. Circulation 2005;112:3680-3687
Copyright © American Heart Association
Arrhythmogenesis
VT/VF and increased rate of afib(upto 20%)
Ventricular arrhythmias and phase two reentry —
• Heterogeneity of myocardial refractory periods in the RV
• This heterogeneity arises from the presence of both normal and abnormal
sodium channels in the same tissue
• Differential impact of the sodium current in the three layers of the
myocardium(Endo, Epi and Mcell)
• Juxtaposition of myocytes with different refractory periods can produce
the triggers that initiate sustained arrhythmias (eg, closely-coupled
premature beats)
• Other factors – such as fibrosis and inflammation
41
AP
42
AP
43
SCN5A gene
Codes for cardiac sodium channel that opens during phase 2 of the action potential.
In Brugada, it opens poorly in RV epicardial cells.
Autosomal dominant inheritance
20-30% of cases have anbl SCN5A
gene.
1
2
0mVolt
s
1
0
80+ mutations, differing prognosis.
-85mVolts
4
4
44
Priori, S. G. et al. Circulation 1999;99:674-681
3
4
Brugada simplified
45
Imbalance b/w depolarizing and repolarizing currents during
phase 2 of the action potential
Most particularly in cells expressing a large, transient outward Ito
current such as epicardial cells of the RV
46
47
Brugada Syndrome is…
A sodium channel abnormality that predisposes to sudden cardiac
death.
Characterized by specific EKG patterns:
• Type I is diagnostic when combined with the right clinical
picture.
• Types II and III raise suspicion for Brugada but they are only
diagnositic if they can be converted to Type I during challenge
with a sodium channel blocker.
• These patterns are dynamic and inducible.
48
Diagnosing the syndrome
ECG definition has become more and more strict.
ST elevation of a coved type of at least 2 mm or ST elevation of
saddleback type if it becomes coved type under stress with antiarrhythmics.
Elevation is always present in V2, and either V1 or V3 (usually
both).
49
Type I- Diagnostic
V1-V3 (as least two leads) ST
segment elevation >2mm,
“coved” shape, inverted T-wave.
Coupled with
• Documented VFib
• Polymorphic VT
• FH of sudden cardiac death <45 yo
• Type I EKG in family members
• VT inducable in EP lab
• Syncope
• Nocturnal agonal respiration
50
Types II and III- Suggestive
II: V1-V3 ST segment elevation
>2mm, “saddleback” shape, pos
or biphasic T.
III: <1 mm elevation, either
coved or saddleback.
51
52
Drugs for diagnosis
Flecainide used now that Ajmaline is no longer available.
Given in an IV in Europe, but maybe 200mg orally but patient must
be monitored for 8 hours because of the long half-life.
Procainamide is effective in unmasking the syndrome, but the
ECGs are much less spectacular.
•May have less specificity and sensitivity than Ajmaline.
54
Sensitivity and specificity
In all patients who had genetic confirmation
• -Ajmaline is very sensitive
Patients’ hearts are different and the positioning of the leads can
play an important role in diagnosis since the syndrome is localized
in RVOT.
•Move up one intercostal position for leads V2 and V3
55
Diagnostic Criteria
1) Appearance of a type-1 ST-segment elevation in more
than one lead (V1-V3), in absence or presence sodium
channel blocking agent
2) Plus one of the following
•
•
•
•
•
•
•
56
Documented ventricular fibrillation (VF)
Polymorphic ventricular tachycardia (VT)
Family history of sudden death (SD) age < 45
Inducibility of ventricular arrhythmias
Presence of a coved-type ECG in family members
Syncope
Nocturnal agonal respiration
Clinical Manifestation
Sudden cardiac arrest may be the first and only clinical event in BS
More common at night, esp when sleeping
Polymorphic VT or VF has been described in up to 17-42% of
diagnosed patients
Up to 20% presents with palpitations or dizziness associated with
SVT
Syncope, neurally mediated
Vagal activity may play an important role
57
Clinical Manifestations: Gender
More common in men than in women (about 8 to 10 times)
Role of sex hormones is currently not well-established
However, it has been postulated that hormones may modify the
ionic membrane currents
Male patients display a higher risk profile
Male sex is an independent predictor of cardiac events (defined as
SD, syncope, ICD shock)
• Based on recent meta-analysis pooling data from 30 studies, including
1500 patients
A, Duonf T, Metz L, et al: Risk stratification of individuals with the Brugada electrocardiogram: a meta-analysis. J
Cardiovasc Electrophysiol 17: 577-583, 2006
58Gehl
FINGER--Registry data
The largest series reported in the FINGER (France, Italy, Netherlands, Germany)
Registry of 1029 patients (654 asymptomatic).
History of SCD conferred an 11 times higher risk of arrhythmic event and history
of syncope
• This was 3.4 times higher rate than asymptomatic patients.
Appropriate ICD shocks occurred in 8 percent of the overall population (2.6
percent per year).
45 patients experienced inappropriate shocks.
59
ECG and Modulating Factors
Typically fluctuates and could be normal
Modulating factors play a major role and also may be responsible
for the ST elevation in genetically predisposed
Premature inactivation of the sodium channel has been shown to be
accentuated at higher temperature
60
Unmasking Brugada
Differential Diagnosis
• Acute MI (especially RV)
(predisposition)
• Hyperkalemia
• Pericarditis
• Hypercalcemia
• PE
• Cocaine
• Dissecting Aortic Aneurism
• Alcohol
• Duchenne muscular dystrophy
• B-blockers
• Mechanical compression of RVOT
• Na channel blockers
– ajmaline, flecainide, procainamide,
• Mediastinal tumor
pilsicainide
• After electical cardioversion
• Ca channel blockers
• Hypothermia
• Anesthetics
• Early repolarization
• Nitrates
• Psychotropic Drugs
– TCA
– SSRI
– Lithium
Role of Drug Challenge
ECG is dynamic and thus the characteristic ECG hallmark may be
concealed
Drug challenge with sodium channel blockers, which increase the
sodium channel dysfunction, has been proposed as a useful tool
for the diagnosis of Brugada syndrome
Ajmaline, flecainide, procainamide, pilsicainide, disopyramide, and
propafenone have been used
Could be used in individuals with suspicious but not diagnostic
EKG
62
ICD
Effective therapy for patients at risk
Annual appropriate shock of up to 3.7%
Reasons for inappropriate shock:
• Sinus tachycardia
• SVT
• T wave oversensing
• VT
63
Pharmacologic Options
Drugs that decrease outward positive currents (Ito inhibitors)
Drugs that increase inward positive current (Ica, Ina)
Amiodarone
64
Pharmacological Options
Quinidine
• Drug of interest in a number of clinical studies
• Ito and Ikr blocker
• ?Possible alternative to ICD implantation
• Adjunctive therapy in patients with ICD and multiple shocks
65
Prognosis
Risk Stratification based on•
Prior History of SCA: 69% recur within 5 years.
•
History of syncope
•
EKG abnormal at baseline or only after drug
•
66
challenge?
Is a SVA inducible in the EP lab?
Prognosis
In 547 patients with type 1 Brugada syndrome with no prior history of SCD, the
probability of SCA or VF during follow-up (average 2 years)
- Overall 8.2% with SCA or VFib.
SVA Noninducible, percent
(95% CI)
SVA Inducible, percent (95%
CI)
- Spontaneously abnormal
4.1 (1.4-11.7)
27.2 (17.3-40.0)
- Abnormal after drug
challenge
1.2 (0.2-6.6)
9.7 (2.3-33.1)
- Spontaneously abnormal
1.8 (0.6-5.1)
14.0 (8.1-23.0)
- Abnormal after drug
challenge
0.5 (0.1-2.7)
4.5 (1.0-17.1)
Prior syncope
EKG
No prior syncope
EKG
67
Brugada, J, Brugada, R, Brugada, P, Circulation 2003; 108:3092
Prognosis and Risk Stratification
Most controversial issue
Goal: to identify factors
that predict the likelihood
of SD
334 patients with mean
follow-up 27+/-29 months
Brugada et al: Long term follow-up of individuals with electrocardiographic pattern of right bundle-branch block and STsegment elevation in precodial leads Circulation 2002; 105; 73-78
Clinical Predictors of Worse Outcome
Symptoms prior to diagnosis
Spontaneous type-1 EKG pattern at baseline
Inducibility of VF during EP
Male sex
Little controversy exists on the value of previous cardiac
arrest as a risk marker for future event
SCN5A mutation have not been proven to be risk marker
in any of the large studies
69
Role of EP Study
70
Brugada et al: Determinants of sudden cardiac death in individuals with EKG pattern of Brugada syndrome and no
previous cardiac arrest. Circulation 108: 3092-3096, 2003
71
Goal
Recognize Brugada I: coved ST segment in V1-V3, >2mm elevation,
inverted T wave.
73
In
the
Era
of
Highly
invasive EP
“We can ablate any arrhythmia”
75
Background
The underlying electrophysiological mechanism that causes an
abnormal ECG pattern and VT/VF in patients with the BrS remains
unelucidated
Several studies have indicated that the right ventricular outflow
tract (RVOT) is likely to be the site of electrophysiological substrate
76
Background cont…
They hypothesized that in patients with BrS who have frequent
recurrent VF episodes, the substrate site is the RVOT, either over
the epicardium or endocardium
Abnormal electrograms would be identified at this location, which
would serve as the target site for catheter ablation
77
Methods and Results
They studied 9 symptomatic patients with the BrS (all
men; median age 38 years) who had recurrent VF
episodes (median 4 episodes) per month, necessitating
ICD discharge.
Electroanatomic mapping of the right ventricle, both
endocardially and epicardially, and epicardial mapping of
the left ventricle were performed in all patients during
sinus rhythm
78
Prolonged AP, fractionation
79
Results
All patients had typical type 1 Brugada ECG pattern and inducible VT/VF
• have unique abnormal low voltage (0.94 +/-0.79 mV), prolonged duration
(132 +/- 48 ms)
• Fractionated late potentials (96 +/- 47 ms beyond QRS complex) clustering
exclusively in the anterior aspect of the RVOT epicardium.
Ablation at these sites rendered VT/VF noninducible (7 of 9
patients(78%) ,P=0.015)
Normalization of the Brugada ECG pattern in 89% P=0.008
Long-term outcomes (20 +/- 6 months) were excellent,
• No recurrent VT/VF
• All patients off medication (except 1 patient on amiodarone).
86
Discussion
The underlying electrophysiological mechanism in patients
with BrS is delayed depolarization over the anterior aspect
of the RVOT epicardium.
Catheter ablation over this abnormal area results in
normalization of the Brugada ECG pattern
• prevents VT/VF, both during electrophysiological studies
• as well as spontaneous recurrent VT/VF episodes in patients
with BrS
87