2014 Life threatening causes of syncope

Transcription

AUTNEU-01649; No of Pages 7
Autonomic Neuroscience: Basic and Clinical xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Autonomic Neuroscience: Basic and Clinical
journal homepage: www.elsevier.com/locate/autneu
Life threatening causes of syncope: Channelopathies
and cardiomyopathies
Adam Herman, Matthew T. Bennett, Santabahnu Chakrabarti, Andrew D. Krahn ⁎
Division of Cardiology, University of British Columbia, Vancouver, BC, Canada
a r t i c l e
i n f o
Article history:
Received 20 March 2014
Received in revised form 4 April 2014
Accepted 14 April 2014
Available online xxxx
Keywords:
Syncope
Channelopathy
Cardiomyopathy
a b s t r a c t
Syncope is common, has a high recurrence rate and carries a risk of morbidity and, dependent on the cause,
mortality. Although the majority of patients with syncope have a benign prognosis, syncope as a result of cardiomyopathy or channelopathy carries a poor prognosis. In addition, the identification of these disorders allows for
the institution of treatments, which are effective at reducing the risk of both syncope and mortality. It is for these
reasons that the identification of a cardiomyopathy or channelopathy in patients with syncope is crucial. This
review article will describe the characteristics of common cardiomyopathies and channelopathies and their
investigation.
© 2014 Elsevier B.V. All rights reserved.
1. Introduction
Syncope is defined as a sudden transient loss of consciousness with
postural failure due to inadequate cerebral perfusion with spontaneous
recovery (Angaran et al., 2011; Bassetti, 2014). Syncope is both common, affecting 6.2 people per 1000 person-years, and associated with
a high rate of recurrence (Soteriades et al., 2002). Furthermore, syncope
carries a risk of morbidity from trauma associated with losing consciousness, and the fear of recurrence, death or that syncope will recur
while driving or swimming (Rose et al., 2000; Van Dijk et al., 2006;
Rose et al., 2009; Sheldon et al., 2009; Rosanio et al., 2013). The majority
of cases of syncope have a benign prognosis, and often do not report
their event to formal medical attention. Despite the common occurrence of syncope and its associated risks, 40% of patients presenting to
the emergency room or primary care setting with an episode of syncope
go home without a diagnosis (Kapoor, 1990). This article will focus on
the exception to the generally benign prognosis, the patients with a
manifest or latent cause of syncope that is life threatening.
2. Etiology
Syncope is classified based on the underlying cause of the episode
(Fig. 1), and tools have been developed to aid in the distinction between
the types of syncope. We refer the reader to the other articles in this
Special Syncope Issue that outline the investigation of syncope-type
symptoms and describe other causes of syncope (Van Dijk and Lim).
⁎ Corresponding author at: Arrhythmia Service, 9th Floor, Gordon & Leslie Diamond
Health Care Centre, 2775 Laurel Street, Vancouver, BC V5Z 1M9, Canada. Tel.: +1 604
875 4111x69821; fax: +1 604 875 5504.
E-mail address: akrahn@mail.ubc.ca (A.D. Krahn).
Syncope associated with structural cardiac disease or a channelopathy is associated with an increased risk of death (Ungar et al., 2010) and
its treatment is often effective in reducing mortality (Khoo et al., 2013).
Although this accounts for a minority of all syncope presentations, a
comprehensive understanding of these conditions is essential. We will
describe the features and mechanisms of the life threatening causes of
syncope associated with cardiomyopathy and channelopathies.
2.1. Cardiomyopathy
The majority of patients with syncope in whom there is concern
regarding underlying structural heart disease will have evidence of
coronary artery disease or non-ischemic dilated cardiomyopathy. This
is typically evident in the clinical history, and is a clear sign of risk of
sudden death attributed to the risk of ventricular arrhythmia. Valvular
heart disease is particularly common in the elderly, and is typically of
concern if there is obstruction to forward flow leading to syncope
(i.e. aortic stenosis with exertional syncope), or when associated with
reduced left ventricular function. As outlined below, all patients presenting with syncope should undergo inquiry as to the presence of underlying structural heart disease, including a resting ECG in all patients,
and an echocardiogram in the vast majority.
Less common causes of cardiomyopathy include infiltrative processes such as amyloidosis or hemochromatosis, and inherited causes such
as hypertrophic cardiomyopathy (HCM) or arrhythmogenic right ventricular cardiomyopathy (ARVC), familial dilated cardiomyopathy and
myotonic dystrophy (Khoo et al., 2013). In most cases, the risk of sudden cardiac death (SCD) due to ventricular arrhythmia is proportional
to the severity of left ventricular dysfunction (Buxton et al., 2000;
Connolly et al., 2000; Katritsis et al., 2013). Detailed discussion of all of
the causes of cardiomyopathy is beyond the scope of this review, but
http://dx.doi.org/10.1016/j.autneu.2014.04.003
1566-0702/© 2014 Elsevier B.V. All rights reserved.
Please cite this article as: Herman, A., et al., Life threatening causes of syncope: Channelopathies and cardiomyopathies, Auton. Neurosci. (2014),
2
A. Herman et al. / Autonomic Neuroscience: Basic and Clinical xxx (2014) xxx–xxx
3. Channelopathies
Channelopathies refer to the group of inherited arrhythmia syndromes that result from mutations in genes encoding proteins that
form or regulate ion channels (Cerrone and Priori, 2011). The currently
identified channelopathies known to cause syncope and sudden death
include Long QT Syndrome (LQTS), Short QT Syndrome (SQTS), Brugada
Syndrome (BrS) and Catecholaminergic Polymorphic Ventricular
Tachycardia (CPVT). As the risk of cardiac arrest is high for patients
with channelopathies presenting with syncope (Rosanio et al., 2013),
identification of these causes of syncope is crucial (Krahn et al., 2013c).
3.1. Long QT Syndrome
Fig. 1. Etiology of syncope.
awareness of the need to exclude underlying cardiomyopathy in evaluating the patient with syncope is crucial to understanding prognosis and
preventing sudden death.
2.2. Familial cardiomyopathies
The cardiomyopathies that may have a familial component account
for a small proportion of all causes of cardiomyopathy, though the
precise proportion is not well described. These include HCM, ARVC,
and cardiomyopathies associated with muscular or neuromuscular
disorders such as Duchenne's, Becker's and myotonic dystrophies or
Friedreich ataxia, Noonan syndrome and lentiginosis (Grunig et al.,
1998; Judge and Johnson, 2008). HCM is the most common inherited
cardiac disease with a prevalence of 1:500 (Maron et al., 1995) and an
autosomal dominant inheritance pattern. It is characterized by the left
ventricular wall thickness ≥15 mm with non-dilated ventricular chambers and microscopic myofibrillar disarray (Gersh et al., 2011). Left ventricular outflow tract obstruction can occur in patients who have septal
hypertrophy, leading to mechanical obstruction to flow during exercise,
or ventricular arrhythmias that lead to syncope or sudden cardiac death
(Khoo et al., 2013). Syncope is a major risk factor for sudden death in
HCM, and should lead to consideration of implantation of an implantable cardioverter defibrillator (ICD).
ARVC is a leading cause of ventricular arrhythmia and sudden death
in young individuals, and can be challenging to diagnose (Marcus et al.,
2010). There is an autosomal dominant inheritance with variable
penetrance and expressivity, and involvement may extend to the left
ventricle. Exercise may be a precipitant of ventricular arrhythmias leading to exertional syncope, and may also contribute to the progression of
disease (Maron et al., 2004; Tan et al., 2005; Basso et al., 2009).
LQTS is an inherited channelopathy characterized by QT interval
prolongation and an increased risk of syncope and sudden death. This
often under diagnosed condition has a prevalence of approximately
1:2500 and a ten-year mortality rate as high as 50% in untreated, symptomatic patients (Sauer et al., 2007; Schwartz et al., 2009; Ackerman
et al., 2011). Typically, syncope usually occurs due to the polymorphic
ventricular tachycardia called torsades de pointes or “twisting of points”
(Roden, 2008) (Fig. 2). The diagnosis of LQTS is often difficult as the QT
interval is dynamic and may not be prolonged at the time of the electrocardiogram. The diagnosis of LQTS is made through a combination of
historical features (syncope, congenital deafness, torsade de pointes
and family history of sudden death), and analysis of the QT interval at
rest and during exercise (Schwartz and Crotti, 2011; Sy et al., 2011b;
Priori et al., 2013b).
Following a clinical diagnosis of LQTS, patients undergo genetic
testing to detect mutations in one of the 13 genes known to cause
LQTS. These mutations can result in dysfunction of potassium, sodium,
and calcium channels and membrane adaptor proteins (Priori et al.,
2013a). LQTS subtypes 1–3 account for 92% of patients with genepositive LQTS (Table 1) (Ackerman et al., 2011). The primary purpose
of genetic testing is both risk stratification and family screening. The
combination of history of syncope or cardiac arrest, gender, QT interval
duration and LQTS subtype can be used to estimate the subsequent risk
of cardiac events (Schwartz et al., 1993; Zareba et al., 1995, 1998; Priori
et al., 2003; Zareba et al., 2003; Ackerman et al., 2011; Schwartz and
Crotti, 2011; Priori et al., 2013a). In particular, recent syncope increases
the risk of cardiac arrest and sudden death across all age categories by 5
to 27 times in patients (Zareba and Cygankiewicz, 2008). For this
reason, the identification of LQTS is crucial in patients presenting with
syncope. Treatment is usually with beta-blockers and infrequent recommendation of an ICD.
SQTS is a distinct syndrome that is analogous to LQTS that differs
due to a gain of function mutations in LQTS related genes, presenting
with familial syncope, atrial arrhythmias and sudden death. SQTS
is characterized by the presence of a QTc interval of ≤ 300 ms or a
QTc b 360 ms with one of the following: a pathogenic mutation, a relative with SQTS, resuscitated idiopathic VF arrest, or a family member
with unexplained sudden death prior to 40 years old (Gollob et al.,
2011b; Priori et al., 2013a).
3.2. Brugada Syndrome
BrS is a channelopathy characterized by the presence of ST elevation
in the right precordial ECG leads in patients with a structurally normal
heart, associated with risk of syncope and sudden death (Fig. 3)
(Brugada and Brugada, 1992). The prevalence varies with ethnicity
with an incidence as high as 1:1000 in Southeast Asians (Antzelevitch
et al., 2005a).
Although BrS is considered an inherited disease, much of the genetics and pathophysiology is poorly understood. The yield of genetic testing is very low in Brugada patients with only 5% of sporadic cases and
20–25% of familial cases having an identifiable mutation. Recent series
3
Fig. 2. ECG of torsades de pointes in a young woman with exercise induced syncope, subsequently diagnosed with type 2 Long QT Syndrome.
have suggested an overall yield in the order of 10–20% (Schulze-Bahr
et al., 2003; Kapplinger et al., 2010; Gollob et al., 2011a). Among cases
with identified mutations, the inheritance pattern is typically autosomal
dominant with variable penetrance. Currently, genetic mutations in 12
genes have been implicated in BrS, with the most commonly identified
mutations involving the SCN5A gene (Crotti et al., 2012; Hofman et al.,
2013) (Fig. 4). Syncope usually occurs while resting, sleeping, with
fever or following exposure to Na+ channel blocker medications, but
rarely during exercise (Priori et al., 2013a). The presence of unexplained
syncope is a marker for risk of SCD leading to a recommendation of
an ICD (Brugada et al., 2005; Priori et al., 2012). The subsequent
annual risk of sudden death in patients with a type 1 Brugada ECG
(spontaneous or induced) is 1.9% per year (Probst et al., 2010).
3.3. Catecholaminergic polymorphic ventricular tachycardia
CPVT is a rare type of channelopathy with an estimated prevalence
of 1:10,000 (Priori et al., 2013a). It has both an autosomal dominant
and autosomal recessive mode of inheritance, with the vast majority
due to mutations in the cardiac ryanodine receptor type 2 (RyR2)
gene (Hayashi et al., 2009; Ackerman et al., 2011). Syncope typically
occurs within the first two decades of life during exercise or during
emotional stress (Leenhardt et al., 1995; Priori et al., 2002; Sumitomo
et al., 2003). Treatment is usually with beta blockers, flecainide and
infrequent recommendation of an ICD.
(cite Lim article here), and syncope risk stratification in the emergency
department (cite Furlan article here).
4.1. Patient history
The history and physical examination suggest the syncope diagnosis
in approximately 50% of cases (Brignole et al., 2006; Van Dijk et al.,
2008) (Table 2). Syncope associated with exercise, swimming, during
strong emotion or loud noises/startle, rest (particularly while lying or
seated) or during sleep particularly in the absence of “warning symptoms” is unusual and should prompt further investigation (Table 3)
(Priori et al., 2013a). In contrast, vasovagal syncope is typically associated with posture, blood or needle phobia, nausea, presyncope before the
episode and the ability to avert syncope by sitting or lying (Gregoratos
et al., 1998). Furthermore, complete recovery without symptoms of
fatigue after the episode is unusual for vasovagal syncope (Priori et al.,
2013a).
4.2. Medications
A careful history of prescription, non-prescription and illicit drug
ingestion is key in patients presenting with syncope. Agents that block
intracardiac ion channels such as those which have IKr blocking properties or cause INa blockade are well recognized to trigger cardiac arrest in
LQTS and BrS, respectively. A list of these medications can be found at
www.qtdrugs.org and www.brugadadrugs.org.
4. Diagnosis
4.3. Family history
Although the prevalence of a familial cardiomyopathy or channelopathy is low, attempting to identify those high-risk syncope patients is
essential as their subsequent risk of cardiac arrest is high. Assessing
for the presence or absence of a channelopathy is attempted through a
focused history and subsequent directed investigations. This often
proves challenging due to the low overall prevalence of channelopathy
and the overlapping characteristics of syncope and investigations in patients with and without a channelopathy as the cause (Krahn et al.,
2013a). This article will focus on the diagnosis of channelopathies in
the context of syncope. The reader is directed to the articles within
this issue that focus on diagnostic algorithm for syncope work-up
A detailed history can identify hereditary mechanisms of syncope.
The family history should include inquiry regarding sudden death,
drowning (suggestive of LQT1 or CPVT) or unexplained accidents,
such as fatal single vehicle accidents or other unexplained catastrophic
events. Epilepsy from secondary seizures, crib death (sudden infant
death syndrome; SIDS) or frequent miscarriages may also be clues to
an inherited mechanism (Table 4). Sudden death in middle age is
often attributed to a “heart attack”, without autopsy evidence of coronary artery disease. A careful review of the details including preceding
syncope or epilepsy may give a clue to an inherited contribution to risk.
Table 1
Long QT Syndrome.
LQTS
Gene
Type
Conditions
ECG
LQT1
KCNQ1
Loss of function in K channel (slow)
Physical or emotional stress
The most likely to have a normal ECG
LQT2
KCNH2
Loss of function in K channel (rapid)
At rest or in association with sudden noises
LQT3
SCN5A
Gain of function in sodium channel
Rest or during sleep
Least likely to have a normal ECG
4
Type 2
Type 1
Type 3
Long QT
Fig. 3. ECG patterns of three types of LQTS.
4.4. Electrocardiogram
4.6. Provocation testing
Despite a modest 5% diagnostic yield, an electrocardiogram (ECG)
should be performed in all patients presenting with syncope (Brignole
et al., 2004), as an abnormal ECG in the presence of syncope carries a
poor prognosis and may elucidate the syncope mechanism (Colivicchi
et al., 2003; Rose et al., 2009). The ECG should be inspected for evidence
of sinus or AV node disease, including fascicular and complete bundle
branch blocks, as well as pathologic Q waves that suggest previous
myocardial infarction. When attempting to identify a channelopathyassociated cause of syncope the ECG is scrutinized for abnormalities in
QT duration, T wave morphology and repolarization (Krahn et al.,
2013b). The normal upper limit of the corrected QT interval is 440 ms;
however, 99% of normal men and women will have a QTc of less than
470 ms and 480 ms, respectively (Taggart et al., 2007). It should be
noted that up to 27% of genotype positive LQTS will have concealed
LQTS (QTc interval b 440 ms) (Tester et al., 2006). Furthermore, the
presence of T wave morphology changes typical of LQTS supports its
diagnosis (Fig. 3, upper panel). There are three patterns of ECG changes
in Brugada Syndrome, illustrated in the lower panel of Fig. 3. These patterns can be dynamic and all three patterns may be seen within the
same patient on serial ECGs (Antzelevitch et al., 2005b). Types 2 and 3
Brugada ECGs only meet the diagnostic criteria for Brugada Syndrome
if they can be converted to a type 1 pattern with provocative testing
(see below). The sensitivity to detect a Brugada pattern is enhanced
by raising the precordial leads by two intercostal spaces. The baseline
ECG in CPVT will be normal.
4.6.1. Exercise testing
Although the primary purpose of exercise testing in patients who
have had syncope is to uncover ischemia, in patients suspected of having a channelopathy it is used to unmask the findings of LQTS and
CPVT. An increase in the QT interval with the brisk tachycardia induced
by standing increases the suspicion of LQTS (Viskin et al.; Walker et al.,
2005; Viskin et al., 2010). Furthermore, the absence of QT shortening
with exercise and the induction of abnormal T wave morphologies
both support the diagnosis of LQTS and provide insight into the specific
LQTS genotype (Chattha et al., 2010; Sy et al., 2010; Wong et al., 2010;
Sy et al., 2011b). The assessment of the QT interval during recovery
further increases the yield of diagnosis of LQTS (Chattha et al., 2010;
Aziz et al., 2011; Horner et al., 2011; Sy et al., 2011b). A QTc greater
than 445 ms at the end of recovery (4 min following cessation of exercise in adults) had a sensitivity of 92% and specificity of 88% at identifying LQT1 and LQT2 individuals from controls (Chattha et al., 2010;
Sy et al., 2011b). Exercise induces ventricular ectopy and may precipitate bidirectional or polymorphic VT at higher exercise intensities in
CPVT (Krahn et al., 2005). Furthermore, these abnormalities will reverse
with cessation of exercise or with intravenous beta-blocker in CPVT. A
positive test is defined if complex ventricular ectopy, bidirectional VT
or polymorphic VT (≥ 3 beats) occur (Haugaa et al., 2010; Sy et al.,
2011a).
4.5. Rhythm surveillance
The general approach to the diagnostic testing of syncope is covered
in the article by Lim et al. (cite Lim article). The gold standard for the
diagnosis of an arrhythmia is a symptom–rhythm correlation during
spontaneous syncope or reminiscent presyncope, which may be accomplished with various forms of short and long-term monitoring technologies (Krahn et al., 2013a). In patients with channelopathies, this may
lead to the specific diagnosis in the event that the ventricular arrhythmia is associated with the respective ECG changes; prolonged QT interval in LQTS, short QT interval in SQTS, bidirectional or polymorphic VT in
CPVT and typical Brugada changes in BrS.
Type 1
4.6.2. Pharmacologic provocation
Pharmacologic “stress” testing is used to provoke latent abnormalities in at risk individuals. Epinephrine infusion is performed to uncover
latent LQTS and CPVT, and Brugada ECGs can be unmasked by a sodium
channel blocker (flecainide, ajmaline, procainamide and pilsicainide).
Techniques for drug provocation are summarized in a review by
Obeyesekere et al. (2011).
Patients with LQT1 will manifest a paradoxical QT response, with an
increase in the absolute QT interval, following epinephrine administration. There are several protocols for administration and interpretation of
epinephrine infusion. The authors favor an absolute QT prolongation of
≥30 ms at 0.10 μg/kg/min epinephrine as the criterion for a positive test
(Vyas et al., 2006; Krahn et al., 2012). It should be noted that concurrent
beta-blockade lowers the diagnostic accuracy of epinephrine infusion. A
Type 2
Type 3
Brugada
Fig. 4. ECG patterns of three types of BrS.
Table 2
Activities leading to syncope.
Table 4
Questions to ask when considering a diagnosis of channelopathy.
Channelopathy
Activity
LQTS
Exercise, swimming, auditory stimuli, strong
emotion, rest and sleep (LQT3 only)
Unknown
Rest or sleep
Exercise or emotional stress
SQTS
Brugada Syndrome
CPVT
5
Does the patient have a history of syncope?
Is there a history of syncope in the patient's family?
Are there any relatives in the patient's family who have had a sudden
unexplained death?
Is there a history of drowning in the patient's family?
Have there been any suspicious motor vehicle accidents?
Conflict of interest
positive epinephrine infusion for CPVT is similar to that outlined above
for exercise testing (Krahn et al., 2005; Sy et al., 2011a).
A type 1 Brugada pattern can be unmasked by sodium channel
blockade due to the varied degree of inhibition of Ito and INa. The overall
sensitivity and specificity for pharmacological provocation with each
agent (flecainide, ajmaline and procainamide) differ due to the degree
of inhibition of Ito and INa and are dependent on whether the patient
has a SCN5A or non-SCN5A mutation. Overall, the sensitivity of provocative tests in patients with a SCN5A mutation (which represents only 20%
of all BrS patients) is estimated to be 71%–85% (Hong et al., 2004;
Meregalli et al., 2006). In the non-SCN5A Brugada Syndrome patients,
procainamide infusion appears to be highly sensitive but there is little
head-to-head comparative data to guide clinical decisions, in part hampered by the lack of access to all drugs in many jurisdictions (Brugada
et al., 2000). There are currently no established provocation tests for
SQTS.
4.7. Genetic testing
Genetic testing in patients with syncope is directed by the clinical
evaluation. We refer the reader to excellent reviews on this subject
(Ackerman et al., 2011; Gollob et al., 2011a). The primary purpose of genetic testing is to allow for family screening and to confirm the diagnosis
if a borderline phenotype associates with a clear disease-causing mutation. Genetic testing, however, is not used to exclude a diagnosis in patients with clear channelopathy associated phenotypes. Furthermore,
genetic testing is fraught with pitfalls including the frequent discovery
of variants of unknown significance and requires careful evaluation of
these results in combination with clinical factors and the results of
previous investigations.
5. Conclusion
Life threatening causes of syncope are infrequent but important, typically associated with underlying structural heart disease or an inherited
channelopathy. Syncope associated with a channelopathy is rare, but
carries a high risk of future syncope and cardiac arrest. A careful history
and physical examination with targeted investigations are the key strategies to identifying and mitigating risk. A systematic approach to the
screening of patients who have had syncope is essential.
The authors have no conflict of interest to declare.
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Table 3
Differentiation between channelopathy syncope, neurogenic syncope and seizures.
History
Channelopathy
Neurogenic
Seizures
Before episode
Precipitant
Presyncope
Relationship of episodes to posture
Palpitations
Prodrome
Onset
Exercise, auditory stimulus, swimming
Sometimes
None
Rare
Presyncope
Sudden
Prolonged standing, fear, emotional stress, pain
Often
Usually standing
Sometimes
Warmth, diaphoresis, nausea, visual blurring
Usually gradual
Sleep deprivation, repeated stimuli
Rare
None
None
Aura
Sudden
During episode
Duration
Seizure activity
Seconds to minutes
Rare
Usually less than a minute
Rare
Variable, can be longer than several minutes
Always
After episode
Time to complete recovery
Seconds to minutes
Minutes
Minutes to hours
6
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