Download Syncope in hypertrophic cardiomyopathy

Europace (2007) 9, 817–822
doi:10.1093/europace/eum093
REVIEW
Syncope in hypertrophic cardiomyopathy: mechanisms
and consequences for treatment
Lynne Williams* and Michael Frenneaux
Department of Cardiovascular Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, West Midlands, UK
Received 28 February 2007; accepted after revision 7 April 2007; online publish-ahead-of-print 23 May 2007
KEYWORDS
Hypertrophic
cardiomyopathy;
Syncope;
Sudden death;
Arrhythmias;
Abnormal vascular control
Hypertrophic cardiomyopathy (HCM) is an inherited disease with marked phenotypic variability that
includes the extent of hypertrophy, the presence and severity of symptoms, and the natural history
of the disease. Symptoms of impaired consciousness (syncope and pre-syncope) occur in approximately
15–25% of patients with hypertrophic cardiomyopathy (HCM). In young patients a history of recurrent
syncope is associated with an increased risk of sudden death. Detailed investigations identify a probable
mechanism in a minority of these, usually paroxysmal atrial fibrillation or ventricular tachycardia. In the
majority, however, no likely mechanism is found despite extensive investigation. Although this may be
the case, it is still of vital importance to exclude potentially treatable causes of syncope.
Introduction
Hypertrophic cardiomyopathy (HCM) is an inherited disease
with marked phenotypic variability that includes the
extent of hypertrophy, the presence and severity of
symptoms, and the natural history of the disease.1
Symptoms of impaired consciousness (syncope and presyncope) occur in 15–25% of the patients with HCM.2–4 In
young patients, a history of recurrent syncope is
associated with an increased risk of sudden death.5–7
Syncope typically occurs in younger patients with smaller
ventricles.8 Impaired consciousness is often provoked by
exercise (either during or after) or by postural change.
However, episodes can occur at rest and are often worse
post-prandially.9,10 Syncope usually occurs without warning
and/or symptoms suggestive of the cause. It is said to be
more common in patients with resting LV outflow tract gradients,11 but this has not been confirmed in other studies.8
Although much attention has focused on the role of obstruction and arrhythmia, detailed investigations identify a probable mechanism in only a minority of patients, usually
paroxysmal atrial fibrillation (AF) or ventricular tachycardia
(VT). In the majority of cases, no likely mechanism is found
despite repeated ambulatory ECG or patient-activated
monitoring, exercise testing, and invasive electrophysiological studies.4,12 In selected patients with obstruction,
septal myectomy or alcohol septal ablation may reduce or
abolish syncope. In those in whom the mechanism cannot
be identified, empiric therapy with amiodarone, a
* Corresponding author. Tel: þ44 121 415 8825; fax: þ44 121 414 3713.
E-mail address: [email protected]
pacemaker, or an implantable cardioverter–defibrillator
(ICD) is commonly employed, but is often unsuccessful in
relieving symptoms.
Principal causes of syncope in hypertrophic
cardiomyopathy
The principal causes of syncope in patients with HCM can be
broadly divided into two underlying mechanisms: arrhythmia
and a primary haemodynamic mechanism (Table 1).
Arrhythmias
Syncope in HCM may be related to atrial or ventricular
tachyarrhythmias or bradyarrhythmias, heart block, or
sinus node dysfunction.
Supraventricular arrhythmias
Atrial fibrillation is the most common sustained arrhythmia
in HCM.13,14 Clinical cohort studies show that AF is reasonably well tolerated by about one-third of patients and is
not an independent predictor of sudden cardiac death
(SCD).13 However, paroxysmal episodes of AF may be responsible for acute clinical deterioration, resulting in syncope or
heart failure that resulted from reduced diastolic filling and
cardiac output—as a consequence of increased ventricular
rate and loss of atrial contraction (and its contribution to
atrial filling) in an already hypertrophied left ventricle
with pre-existing impaired relaxation and compliance.13,14
Other supraventricular arrhythmias may result in syncope
& The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: [email protected]
818
Table 1 Mechanisms for syncope in hypertrophic cardiomyopathy
Arrhythmia
Paroxysmal atrial fibrillation/supraventricular tachycardia
Complete heart block/sinus node dysfunction
Sustained ventricular tachycardia
Primary haemodynamic mechanism
Left ventricular outflow tract obstruction
Abnormal vascular control mechanisms leading to episodes of
hypotension due to inappropriate vasodilatation
Hypotension due to impaired filling when preload is reduced
in the setting of diastolic dysfunction
via similar mechanisms. In a study by Schiavone et al.,15
24-hour Holter monitoring and electrophysiology studies
(EPS) were performed on 26 patients with HCM, some with
an evidence of LV outflow tract obstruction and some with
a history of syncope, in order to predict their vulnerability
to syncope and to potentially malignant arrhythmias.
Holter monitoring demonstrated supraventricular tachycardia (SVT) in 9/26 patients, whereas atrial programmed electrical stimulation (PES) induced SVT in 17/26 patients. Of
the 17 patients, nine had symptomatic hypotension with
SVT while lying supine. The authors concluded that atrial
PES-induced SVT with hypotension best predicted a history
of syncope in these patients.15
Fananapazir et al. performed EPS in 155 patients with
HCM. Indications for EPS were cardiac arrest in 22 patients,
syncope in 55 patients, pre-syncope in 37 patients, asymptomatic VT in 24 patients, palpitations in 10 patients, and a
strong family history of SCD in 7 patients. Electrophysiology abnormalities were present in 126 (81%) patients. A
high prevalence of abnormal sinus-node function (66%) and
His–Purkinje (HV) conduction (30%) was noted. The most
commonly induced supraventricular arrhythmias were
atrial re-entrant tachycardia and AF (10 and 11% of patients,
respectively). Accessory atrioventricular (AV) pathways
were present in seven (5%) patients.16
Ventricular arrhythmias
Non-sustained ventricular tachycardia (NSVT) is common in
HCM, but is not usually associated with symptoms. Indeed,
typically episodes occur most commonly during sleep.17–19
In a study by Nienaber et al.,8 NSVT proved to be nonspecific as a predictor for syncope. The authors studied 27
patients with HCM and stratified them into two groups:
those with witnessed documented syncope and those
without syncope. The incidence of premature ventricular
beats, complex ventricular ectopic activity, and NSVT was
similar in patients with or without syncope.8 This is
indirectly supported by previous data17,18,20,21 confirming
that NSVT in HCM is usually slow and short-lasting, thus
not itself the cause of syncope. In contrast, sustained VT is
relatively uncommon in HCM, but can be a cause of
syncope. It can arise from a distal aneurysm in patients
with mid-cavity obstruction.22 Programmed electrical stimulation studies appear unhelpful in identifying whether ventricular arrhythmia is the cause of syncope in patients with
HCM. Kuck et al. performed PES in 54 consecutive patients
with HCM. The type and incidence of induced ventricular
arrhythmias did not differ between the ‘symptomatic
(syncope)’ and ‘asymptomatic (no syncope)’ groups. They
L. Williams and M. Frenneux
concluded that PES induced the same type of ventricular
arrhythmia in ‘symptomatic’ and ‘asymptomatic’, with no
causal relation between induction of arrhythmias and the
incidence of syncope.23
Primary haemodynamic mechanisms for syncope
Various triggers may potentially precipitate syncope and SCD
in patients with HCM. However, there is a growing body
of evidence demonstrating that disturbed reflex control of
the vasculature is a frequent abnormality in patients
with HCM. This abnormal control may result in sudden inappropriate vasodilatation, resulting in episodes of hypotension, which may in turn lead to recurrent syncope and act
as a trigger for sudden death. Almost 50% of SCD’s in HCM
patients occur during or soon after exercise.24 A small
study of beta-blocker therapy published in 1970 noted exercise hypotension in some patients,25 but the significance of
this observation was largely ignored initially. It is now apparent that abnormal blood pressure responses (ABPRs) on exercise are seen in a substantial proportion of patients and
confer an increased risk of SCD.26,27
Abnormal blood pressure responses during exercise in
hypertrophic cardiomyopathy patients
It is now clear that a significant proportion of patients have
ABPRs during maximal treadmill exercise. This was first
described by Edwards et al. 25 in 1970 in a small study and
was subsequently confirmed by us in a consecutive series
of 129 patients attending a tertiary referral centre.26 An
ABPR is defined as either a failure of systolic BP to rise by
at least 20 mmHg during maximal treadmill exercise, or as
a fall of .20 mmHg at peak exercise compared with preexercise levels or a reading obtained earlier in exercise.
According to these criteria, we found that approximately
one-third of patients had an ABPR on exercise. In a subsequent study of 126 patients attending a community-based
hospital, this ABPR was observed in 22%.28
Left ventricular outflow tract obstruction in hypertrophic
cardiomyopathy
Outflow tract obstruction was initially thought to be the
usual cause of syncope and hypotension on exertion.
Although no association between ABPR and resting LV
outflow tract obstruction (LVOTO) has been found, this
does not exclude dynamic LVOTO as an important mechanism, and in our clinical experience, we have certainly
encountered some patients in whom cardiac output limitation was the dominant mechanism of ABPR during exercise.
Indeed, recent studies have reported a normalization of
ABPR following alcohol septal ablation for LVOTO.29 In a subsequent review of 65 patients who had undergone septal
myectomy between 1986 and 1992, significant improvement
was observed in 86% of patients with pre-syncope preprocedure and in 100% of patients with syncope.30
However, in our experience, an exaggerated fall in systemic
vascular resistance appears to be a major component in a
substantial proportion of patients.
Abnormal vascular control mechanisms in hypertrophic
cardiomyopathy
We performed invasive haemodynamic studies in 14 patients
with HCM and a normal blood pressure response and 14 with
Syncope in hypertrophic cardiomyopathy
HCM and an ABPR. In this highly selected study population,
the increase in cardiac output was marginally (but significantly) higher in the ABPR group, and by implication, ABPR
was due to an exaggerated fall in systemic vascular resistance during exercise.26 In a subsequent study of 103 consecutive patients with HCM, we examined the vascular
responses in a non-exercising vascular bed during supine
cycle exercise and the blood pressure response during
maximal treadmill exercise. Forearm vascular resistance
(FVR) was measured using strain gauge plethysmography.
In normal controls, there is an increase in FVR during leg
exercise (vasoconstriction in the non-exercising muscle
bed). In contrast, in one-third of the patients with HCM,
FVR failed to increase or paradoxically decreased during
exercise. This abnormal pattern was strongly associated
with ABPR during maximal treadmill exercise.31 These data
indicate that ABPR may, in most cases, be at least in part
due to an exaggerated fall in systemic vascular resistance
related to inappropriate vasodilatation or a failure of vasoconstriction in non-exercising vascular beds. This does not
exclude an abnormal cardiac output response as the dominant mechanism or as a contributory mechanism in some
patients. A normal ventricle might be expected to increase
cardiac output to a greater extent in the face of a fall in systemic vascular resistance than was seen in HCM patients.
Consistent with this, we have shown that patients with
vasovagal syncope frequently demonstrate an abnormal
fall in FVR during cycle exercise, yet ABPR was relatively
uncommon in these patients who have normal ventricles.32
Several factors may contribute to the inability to
increase cardiac output appropriately in the face of an exaggerated fall in systemic vascular resistance. As mentioned
earlier, dynamic outflow tract obstruction cannot be
excluded as an important mechanism. However, other
mechanisms may contribute. The normal increase in stroke
volume on exercise results in part from an increase in
pre-load (end-diastolic volume). We have shown that
patients with HCM frequently exhibit a failure of splenic
venoconstriction during exercise (presumably via a
mechanism similar to that responsible for the failure of
resistance vessel constriction).33 This, together with the
diastolic dysfunction, which characterizes HCM, may
markedly limit the ability to augment cardiac output in
some patients.
We recently reported that paroxetine ameliorated both
ABPR and abnormal forearm vascular responses during
lower body negative pressure (LBNP) and that clonidine
and propanolol ameliorated the latter but not the
former.34 Paroxetine is a highly selective serotonin (5-HT)
reuptake inhibitor and has been reported to provide functional improvement in patients with vasovagal syncope.
We assessed the frequency of abnormal forearm vasodilator
responses to LBNP in 21 non-obstructive HCM patients with
an ABPR during exercise testing and the effects of three
drugs used to treat vasovagal syncope (propanolol, clonidine, and paroxetine) in a double-blind crossover study. By
reversing or attenuating the ABPR during exercise, and
their abnormal vascular response during abrupt reductions
in central blood volume, Paroxetine may potentially
reduce the number or severity of hypotensive episodes
and/or syncope in patients with HCM and ABPR, and might
conceivably reduce the risk of SCD, but this remains to be
evaluated.
819
Potential mechanisms for abnormal vascular control:
abnormal baroreflex sensitivity
In healthy subjects during exercise, central command and
skeletal muscle metaboreceptor inputs increase vasoconstrictor sympathetic outflow from the brainstem, and this
is responsible for vasoconstriction in non-exercising vascular
beds. Vasodilatation in exercising vascular beds appears to
be mediated by metabolic products of exercise.35 In the
1970’s, Mark et al. reported that exercise syncope in
patients with aortic stenosis was associated with an abnormal fall in FVR during leg exercise (similar to that seen in
HCM patients) and that this reverted to a normal response
after aortic valve replacement.36 In another study in anaesthetized dogs, this group showed that inflation of a balloon
in the left ventricle resulted in a fall in skeletal muscle vascular resistance, whereas balloon inflation in the left atrium
had no effect.37 They concluded that the abnormal exercise
vascular response seen in patients with aortic stenosis was
most likely the result of enhanced activation of stretchsensitive LV mechanoreceptors due to increased LV wall
stresses (which could be attributed to increased intracavitary pressures resulting from the aortic stenosis).
Activation of these mechanoreceptors, which relay to the
brainstem via non-myelinated afferents, has an inhibitory
effect on sympathetic outflow from the brainstem, and
this may overcome the input from central command and
skeletal metaboreceptors, leading to inappropriate
vasodilation.
These findings parallel those in HCM patients, but the role
of LV mechanoreceptors in generating abnormal vascular
responses is inferred rather than proven. Increased LV wall
stresses might be expected to occur in HCM for three
reasons:
(i) the presence of LVOTO;
(ii) the presence of patchy myocyte disarray and/or fibrosis causing localized areas of increased wall stress;
(iii) the presence of subendocardial ischaemia.38
There is, however, further evidence pointing to the dysfunction of the LV mechanoreceptors in HCM. Central
blood volume unloading, which occurs on assuming an
upright posture (as a result of pooling of blood in the
pelvic and lower limb veins), normally causes reflex compensatory adjustments that result in an increase in systemic
vascular resistance, venoconstriction, and a modest
increase in the heart rate in order to maintain cardiac
output and blood pressure. In health, these adjustments
ensure that the fall in blood pressure is small and brief.
The initial fall in cardiac chamber size and blood pressure
results in reduced afferent input from cardiopulmonary
and arterial baroreceptors, respectively, which results in
increased sympathetic outflow from the brainstem. Lesser
degrees of central blood volume unloading, which are insufficient to reduce blood pressure, can be achieved by the
application of LBNP. A marked increase in FVR is seen,
despite the absence of any fall in blood pressure. Available
evidence suggests that this response is predominantly
mediated via inactivation of LV mechanoreceptors.39 The
reflex is absent in the denervated transplanted heart.40
We showed that during application of LBNP, in approximately
one-third of patients, there was paradoxical forearm vasodilatation. There was no evidence of an abnormality of central
or efferent mechanisms. Furthermore, the function of
820
carotid baroreceptors was assessed and was shown to be
normal.41 We considered that the most likely explanation
for these observations was a failure of the normal inactivation (and in some cases, paradoxical activation) of LV
mechanoreceptors during central blood volume unloading
in these patients. The mechanism of this abnormality is
unclear, but heterogeneous strain changes associated with
the patchy myocyte disarray and fibrosis may provide a
substrate.
Abnormal vascular control: episodic hypotension and
recurrent syncope
As noted above, multiple mechanisms may be responsible
for recurrent syncope in patients with HCM, including
arrhythmia and dynamic LVOTO, yet despite extensive investigation, the cause is not identified in the majority of
patients.4,12 We recently assessed a highly selected series
of 18 HCM patients with recurrent pre-syncope and/or
syncope for which no cause had been identified despite
extensive investigation. This group was compared with 11
HCM patients without such a history. Beat-by-beat blood
pressure waveforms were recorded using a Portapres
system for a period of 24 h. Recurrent abrupt spontaneous
episodes of hypotension without an associated reflex tachycardia were observed in eight of the patients with a history
of syncope, but in none of those without such a history.
Sixty per cent of these episodes were associated with a
period of impaired consciousness. Using a validated transfer
function, we were able to show that systemic vascular
resistance fell markedly during these episodes, whereas
stroke volume and cardiac output did not change during
these episodes, and by implication, the hypotension was
due to vasodilatation. Consistent with the proposed neurally
mediated mechanism, there was no reflex increase in the
heart rate during these episodes, indicating an abnormal
baroreflex response.
Investigation of recurrent syncope in
hypertrophic cardiomyopathy
Symptoms of impaired consciousness occur in 15–25% of the
patients with HCM. In young patients, a history of recurrent
syncope is associated with an increased risk of SCD. Syncope
usually occurs without warning or prior symptoms suggestive
of the cause. Detailed investigations identify a probable
mechanism in a minority of these, usually paroxysmal AF
or VT. In the majority of cases, however, no likely mechanism is found despite repeated 24-h ambulatory ECG or
patient-activated monitoring, exercise testing, and invasive
electrophysiological testing. Although this may be the case,
it is still of vital importance to exclude the potentially treatable causes of syncope. Investigations can be divided into
those for arrhythmia causes and those assessing primary
haemodynamic mechanisms.
L. Williams and M. Frenneux
mechanism of supraventricular arrhythmias. As noted
above, PES is usually unhelpful.
Primary haemodynamic mechanisms
It is important to exclude dynamic LVOTO as a cause of
syncope. This is best achieved by means of exercise echocardiography. All patients should undergo cardiopulmonary
exercise testing with an assessment of the blood pressure
to exercise. Although not routinely available, beat-by-beat
ambulatory blood pressure monitoring (e.g. by Portapres)
can demonstrate inappropriate vasodilatation and its
relation to clinical symptoms.
Management of syncope in hypertrophic
cardiomyopathy
The following principles of management should be adhered
to all patients with HCM. It is vital to try and establish the
mechanism of syncope, although as mentioned earlier, in
the majority of cases, no cause can be identified. Where
possible, treatment should be based on the identified mechanism. Empiric treatment with amiodarone, a pacemaker, or
an ICD is commonly employed, but is often unsuccessful in
relieving symptoms. However, there are some targetspecific treatments available in patients in whom the mechanism underlying symptoms has been identified.
Supraventricular arrhythmias
Most symptomatic arrhythmias are supraventricular, which
develop in association with atrial dilatation. Amiodarone is
the most effective agent for reducing the occurrence of
paroxysmal AF and for maintaining sinus rhythm following
cardioversion in patients with new-onset AF. In patients
with established trail fibrillation, rate control can usually
be achieved with verapamil or a beta-blocker. Occasionally, AV nodal ablation with permanent pacemaker implantation is required. Unless a contra-indication exists, patients
with established or paroxysmal AF should receive
anticoagulation.
Ventricular tachycardia
Sustained VT, although rare in patients with HCM, should be
treated with amiodarone or an implantable cardioverter–
defibrillator. Non-sustained ventricular tachycardia is not
usually a cause of syncope but is one risk factor for SCD.
In the absence of other risk factors, treatment with amiodarone is appropriate, but when NSVT occurs in combination
with one or more other risk factors for SCD (as listed below),
an ICD is the most appropriate therapy.
Conduction disturbances
Arrhythmic causes
A resting ECG should be performed to exclude the evidence
of conduction disease, and all patients should undergo
ambulatory ECG monitoring for a period of 48 h. In rare
cases, an implantable recorder may be useful for identifying
an arrhythmic basis. Electrophysiology studies are not routinely performed, but may be necessary to identify the
Premature conduction disease and chronotropic incompetence may cause exercise limitation and symptoms of
impaired consciousness in patients with HCM. Any kind of
bradyarrhythmia or conduction disturbance that is considered to cause haemodynamic decompensation should be
considered for pacemaker implantation according to
current guidelines.42
Syncope in hypertrophic cardiomyopathy
Relief of left ventricular outflow tract obstruction
Initial treatment of symptomatic patients with outflow tract
obstruction is pharmacological, with beta-blockade and, if
necessary, addition of Disopyramide.43 The negative inotropic effects of this combination are usually effective at reducing the gradient and symptoms if high doses of
disopyramide can be maintained. The anticholinergic side
effects are often well tolerated in young patients, whereas
this pharmacological approach is usually not practical in
older males because of urinary retention. If medical
therapy fails, then surgical myectomy is effective (.80%
success), and, in experienced centres, pre-operative mortality rates during the past decade have been below 2%
(1% in high volume centres). Surgery has also been
shown to reduce the symptoms of presyncope and
syncope.30 Alcohol septal ablation has also been reported
to reduce syncopal symptoms in selected patients44 but mortality is no lower than surgery, the risk of procedure-related
complete heart block higher,45,46 and there have been concerns raised about the long-term risk of post-infarct remodelling.47,48 The selection of patients for myectomy vs.
alcohol septal ablation therefore remains controversial.
Recent studies have reported a normalization of ABPR
following alcohol septal ablation for outflow tract
obstruction.29
Initial reports suggested that short AV delay right ventricular pacing could relieve the symptoms in patients with
obstructive HCM, but subsequently two large studies
reported that much of this was a ‘placebo’ effect.
Nevertheless, there are clear ‘responders’. Clinically, older
patients with syncope seem most likely to be responders.
821
risk factor profile of patients with HCM is much more accurately assessed in terms of their total burden of risk factors.
The following algorithm for risk stratification should be
applied to individual patients.
(i) Patients with a prior cardiac arrest or spontaneous sustained VT are at high risk and should be considered for
prophylactic therapy with an ICD.
(ii) In the absence of such a history, risk is probably best
assessed on the basis of the total number of the following risk factors:
(a) maximum wall thickness .30 mm;
(b) systolic blood pressure response measured at oneminute interval during maximal upright exercise in
patients, 40 years of age (ABPR ¼ failure to
increase by .25 mmHg or a fall from peak values
during continued exercise of .15 mmHg);
(c) non-sustained VT during 48-h ambulatory ECG
monitoring;
(d) a history of at least one SCD in a relative before
the age of 45 years, together with a history of
syncope;
(e) a resting peak instantaneous LV outflow tract gradient of .30 mmHg.
Patients with no risk factors can be strongly reassured.
Those with two or more risk factors are at high risk and
should be considered for prophylactic therapy with an ICD
and/or amiodarone. Those with a single risk factor are at
intermediate risk.
Summary
Abnormal vascular responses
As mentioned earlier, we have recently demonstrated in a
randomized double-blind placebo-controlled study that
exercise blood pressure responses were improved by perhexiline therapy and that abnormal forearm vascular
responses during the application of LBNP were attenuated
or normalized by propanolol, clonidine, and paroxetine. By
reversing or attenuating the ABPR during exercise, and the
abnormal vascular response during abrupt reduction in
central blood volume, paroxetine may potentially reduce
the number or the severity of hypotensive episodes
and/or syncope in patients with HCM and ABPR and might
conceivably reduce the risk of SCD, but this remains to be
elucidated.
Risk stratification and syncope as a risk factor
in hypertrophic cardiomyopathy
HCM is an important cause of SCD. Many of these SCDs occur
in patients with minimal or no symptoms. With the development of the ICD, effective preventive therapy is now available. The challenge is to distinguish high-risk from low-risk
patients in order to target prophylactic therapy to those
at risk.
Several risk factors have been shown to be associated with
an increased risk of sudden death in patients with HCM. The
predictive accuracy of each of these risk factors is generally
low during medium-term follow-up. Consequently, the use
of single risk factors to guide risk factor stratification is
unhelpful. Elliott et al. 2 have argued persuasively that the
Symptoms of impaired consciousness (syncope and presyncope) occur in 15–25% of patients with HCM, and in
young patients with a history of recurrent syncope are
associated with an increased risk of SCD. Detailed investigations identify a probable mechanism in a minority of
these, usually paroxysmal AF or VT. In the majority of
cases, however, no likely mechanism is found despite extensive investigation. Although this may be the case, it is still of
vital importance to exclude the potentially treatable causes
of syncope.
Conflict of interest: none declared
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