Silent ischaemic brain lesions related to atrial high rate episodes in patients with cardiac implantable electronic devices
Silent ischaemic brain lesions related to atrial high rate episodes in patients with cardiac implantable electronic devices
Juan Benezet-Mazuecos 0
Jose? Manuel Rubio 0
Marcelino Corte? s 0
Jose? Antonio Iglesias 0
Soraya Calle 0
Juan Jose? de la Vieja 0
Miguel Angel Quin? ones 0
Pepa Sanchez-Borque 0
Elena de la Cruz 0
Adriana Espejo 0
Jer o?nimo Farr e? 0
0 Department of Cardiology, Hospital Universitario Fundacio ?n Jime ?nez D ??az - IDC salud, Universidad Auto ?noma de Madrid, Avenida Reyes Cat o ?licos 2 , Madrid 28040 , Spain
Aims Monitoring capabilities of cardiac implantable electronic devices have revealed that a large proportion of patients present silent atrial fibrillation (AF) detected as atrial high rate episodes (AHREs). Atrial high rate episodes .5 min have been linked to increased risk of clinical stroke, but a high proportion of ischaemic brain lesions (IBLs) could be subclinical. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods We prospectively analysed the incidence of AHRE . 5 min in 109 patients (56% men, aged 74 + 9 years) and the presand results ence of silent IBL on computed tomography (CT) scan. Mean CHADS2 and CHA2DS2VASc scores were 2.3 + 1.3 and 3.9 + 1.6, respectively. Seventy-five patients (69%) had no history of AF or stroke/transient ischaemic attack (TIA). After 12 months, 28 patients (25.7%) showed at least one AHRE. Patients with AHREs were more likely to have history of AF. Computed tomography scan showed silent IBL in 28 (25.7%). The presence of IBL was significantly related to older patients, prior history of AF or stroke/TIA, higher CHADS2 or CHA2DS2VASc scores, and the presence of AHRE. Multivariable analysis demonstrated that AHRE was an independent predictor for silent IBL in overall population [hazard ratio (HR) 3.05 (1.06 - 8.81; P , 0.05)] but also in patients without prior history of AF or stroke/TIA [HR 9.76 (1.76 - 54.07; P , 0.05)]. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion Cardiac implantable electronic devices can accurately detect AF as AHRE. Atrial high rate episodes were associated to a higher incidence of silent IBL on CT scan. Atrial high rate episodes represent a kind of silent AF where management recommendations are lacking despite the fact that a higher embolic risk is present. - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Atrial fibrillation (AF) is recognized as the most prevalent cardiac
arrhythmia and is associated with substantial complications and
healthcare costs.1,2 Assessment of the prevalence of silent paroxysmal AF
represents a challenge, since the arrhythmia may be brief, completely
asymptomatic, and difficult to detect. Lack of symptoms from AF
should not be equated to lack of risk of thrombo-embolic
complications due to AF, which is probably present to the same degree as in
symptomatic AF.3 The stroke risk conferred by paroxysmal AF has
been considered to be the same as continuous AF.4 Stroke can be
the first symptom of a ?silent? AF previously unrecognized.5 Cerebral
computed tomography (CT) and magnetic resonance imaging (MRI)
are useful diagnostic techniques detecting both symptomatic and
silent ischaemic brain lesions (IBLs) in patients with AF.6 Identification
of short episodes of paroxysmal AF, even in the absence of
symptoms, therefore may be important to permit early intervention.
Cardiac implantable electronic devices (CIEDs) have shown
reliable AF detection as atrial high rate episodes (AHREs).7 The presence
of AHRE has been related to increased risk of stroke and systemic
embolism.8 ? 10 These studies have evaluated the occurrence of
symptomatic clinical events but the real embolic risk could be
? Identification of paroxysmal atrial fibrillation (AF), even in the
absence of symptoms, is crucial to permit an early intervention
avoiding a thrombo-embolic event as first symptom.
? Multiple studies have shown that atrial high rate episodes
(AHREs) detected in cardiac implantable electronic devices
(CIEDs) are related to an increased risk of stroke.
? These studies have evaluated symptomatic events but
brain-imaging techniques have shown that silent cerebral
infarcts are frequently seen in asymptomatic patients with AF.
? Subsequently, the embolic risk attributed to AHRE could be
? Our study is the first study that evaluates the relation between
the incidence of AHRE and the presence of silent ischaemic
brain lesions on computed tomography (CT) scan.
? Our data also showed that the presence of AHRE . 5 min in
this selected population of patients with CIED was an
independent risk factor associated to silent ischaemic brain lesions
detected on CT scan in patients without prior history of AF
or stroke/transient ischaemic attack (odds ratio 5.83).
underestimated. Silent or subclinical IBL can be detected by CT scan
and could help to reflect a more real perspective of the embolic risk
these patients are exposed to.
Patients in sinus rhythm, with or without history of previous episodes of
AF and with St Jude Medical dual-chamber pacemakers (PMs),
implantable cardioverter-defibrillators (ICDs), and devices for cardiac
resynchronization therapy (CRT) capable of atrial activity monitoring were
included in the study. Baseline patient?s characteristics including
cardiovascular risk factors, prior heart disease, or atrial tachyarrhythmia,
indications for CIED implantation, and medications were recorded.
The study protocol was presented and approved by the Ethics
Committee of our Institution. Patients were recruited after implantation or
in the scheduled follow-up visits from February 2012. At inclusion,
patients were informed of the investigational purpose of the study,
asked to perform a brain CT scan examination (Phillips Brilliance 64
CT Scanner). and informed consent was obtained. Scheduled PM
checkups were planned at 3 months after inclusion and every year. All the PM
check-up data were downloaded in the patient medical history. No
special surveillance was protocolized in patients presenting AHRE
It is the protocol of our Arrhythmia Unit to avoid right ventricular
pacing in all the dual-chamber PMs prolonging the AV interval and using
other dedicated algorithms when necessary. Implantable
cardioverterdefibrillators were programmed with back-up pacing (VDI 40 b.p.m.)
conserving atrial sensing. Cardiac resynchronization therapy are
programmed with an adequate AV interval to achieve .95% of biventricular
For the purpose of this investigation, AHRE were defined as episodes
of atrial rate ?225 b.p.m. with a minimum duration of 5 min or more.
Intracavitary electrograms acquisition was programmed to confirm AF
based on atrial electrograms during the episodes.
We analysed prospectively the incidence of AHRE . 5 min compatible
with AF in patients in sinus rhythm with dual-chamber cardiac devices
and the presence of IBL on CT scan.
Device and clinical evaluation
From February 2012, all the subsequent scheduled PM check-ups were
reviewed. Pacemaker atrial stimulation/sense parameters, atrial lead
impedance, percentages of atrial and ventricular pacing, AHRE, automatic
mode switch episodes, and noise episodes were recorded.
A clinical evaluation was also performed including symptoms, hospital/
emergency department admissions, changes in treatment
(antiarrhythmic and antithrombotic treatment), electrocardiogram (ECG)
documentation of AF, and mortality.
Brain computed tomography scan evaluation
Brain infarcts are described as focal lesions with roughly the same
intensity as cerebrospinal fluid on CT scan. Although sensitivity for infarct
detection is better for MRI compared with CT, particularly for small lesions
located in the basal ganglia, using MRI in asymptomatic patients with
implantable cardiac electronic devices is not recommended and it was
not considered in our protocol.
All CT scans were performed at inclusion and evaluated blindly by
consultant neuroradiologists in our institution with special attention to the
number and size of low-density areas compatible with infarcts. Lesion
size was measured and ischaemic lesions on brain CT scan were
described as those focal lesions that were 3 mm or larger with sharp
demarcation from surrounding tissue. Infarcts were classed as silent if
they lack stroke-like symptoms after questioning patient combined
with evidence from medical records in the clinical history. In patients
with prior clinical stroke/transient ischaemic attack (TIA), the responsible
lesions were excluded and only new lesions or when multiple were
Data were subjected to descriptive statistical analysis, via frequency
measurements (absolute frequencies and percentages) for qualitative
variables, and via means and standard deviations for quantitative variables.
Univariate analysis of the quantitative variables was performed using
the Student?s t-test when their distribution was normal and the Mann ?
Whitney U test when they were not. The qualitative variables were
analysed using the x2 or the Fisher?s exact test. Multivariate analysis with
logistic regression (backward stepwise) was employed to determine
whether the association between the IBL on CT scan and AHRE was
influenced by the baseline characteristics of the groups (confounding factors).
Interactions could not be evaluated in multivariate analysis owing to the
small sample size. From the collection of baseline variables shown in
Table 1, those with the potential to act as confounding factors were
selected first in terms of their clinical and biological plausibility, and
secondly in terms of the statistical criterion of Mickey excluding all those
variables that in univariate analysis returned an association with the response
reflected by a value of P . 0.20. Due to the strong relation between
CHADS2 and CHA2DS2VASc scores (both statistically related to the
presence of IBL on CT scan in the univariate analysis), we decided to
exclude CHADS2 score in the multivariate analysis to avoid redundant
variables, maintaining CHA2DS2VASc score that is considered to
Continuous variables are presented as median + SD.
Categorical variables are presented as number (%).
AHRE, atrial high rate episode; TIA, transient ischaemic attack. Bold values show variables showing a statistically significant relationship.
provide a better thrombo-embolic risk stratification. Therefore, the
variables included in the multivariate analysis performed in the overall study
population were: age, high blood pressure, CHA2DS2VASc score,
smallvessel disease on CT scan, chronic kidney disease, history of prior AF,
prior stroke/TIA, and AHRE . 5 min. The variables included in the
multivariate analysis performed in the subgroup of patients without prior
history of AF or stroke/TIA were: age, CHA2DS2VASc score, structural
heart disease, and AHRE . 5 min. The magnitude of the effects of the
variables was expressed in the form of odds ratio (OR) and 95%
confidence limits (95% CI).
From February 2012 to February 2014, 109 consecutive patients
(61 men, 56%) were enrolled in the study. We included 97 PMs
(89%), 7 ICDs (6%), and 5 CRTs (5%). The main indication for PM
implantation was sinus node disease (51%). The mean age was 74 + 9
years (range 26 ? 94). In 74 patients (68%), there was no evidence
of underlying structural heart disease. Prior history of AF was
present in 22 patients (20%) and prior stroke/TIA in 21 patients
(19%). Seventy-five patients (69%) had no prior history of AF or
stroke/TIA. Mean CHADS2 and CHA2DS2VASc scores were 2.3 +
1.3 and 3.9 + 1.6, respectively, reflecting a moderately high expected
stroke risk. The baseline characteristics of the study population are
provided in Table 1.
Atrial high rate episodes
After a mean follow-up of 17 + 6 months, 28 patients (25.7%)
showed at least one AHRE . 5 min. Fifteen patients (13.7%)
presented at least one episode at 3 months. Episodes last 5 min to 1 h
in 10 patients, 1 ? 12 h in 10 patients, 12 ? 24 h in 2 patients, and
.24 h in 6 patients. Patients with AHREs were more likely to have
a history of AF, anticoagulation or antiarrhythmic treatment, and
prior stroke or TIA than patients without AHRE, Table 1. After
excluding patients with prior AF, there were no statistical differences related
to the presence of AHRE attending to baseline characteristics.
Ischaemic brain lesions on computed
Brain CT scans were evaluated as normal in 81 patients (74.3%).
Twenty-eight patients (25.7%) presented one or more small silent
IBL. Among these patients, 10 patients (35%) had prior AF and 14
patients (50%) had prior stroke/TIA. On the other hand, 11 patients
(39%) had none of both antecedents, Table 2. The presence of IBL on
CT scan was significantly related to older patients, prior history of
AF or stroke/TIA, higher CHADS2 or CHA2DS2VASc scores, and the
presence of AHRE . 5 min at 12 months. There were no differences
related to the duration of the AHRE in patients with and without IBL.
In 87 patients (80%) without prior history of AF, 8 patients showing
AHRE . 5 min (47%) presented one or more IBL on CT scan
compared with 10 of 70 patients without AHRE (14%), P ? 0.005.
The results of the univariate analysis are shown in Table 3. The
presence of IBL on CT scan was associated to the age, CHADS2 or
CHA2DS2VASc scores, and prior history of AF or stroke/TIA. The
presence of AHRE . 5 min was associated with an increased risk
of IBL in both overall population [OR 3.04 (1.20 ? 7.70; P , 0.05)]
and patients without prior history of AF or stroke/TIA [OR 5.83
(1.44 ? 26.63; P , 0.05)].
Multivariable analysis demonstrated that the presence of AHRE .
5 min [hazard ratio 3.05 (1.06 ? 8.81; P , 0.05)] and CHA2DS2VASc
score [hazard ratio 2.29 (1.55 ? 3.37; P , 0.001)] were independent
predictors of IBL in overall population. In the subgroup of patients
without prior history of AF or stroke/TIA, AHRE . 5 min was also
an independent predictor of IBL [hazard ratio 9.76 (1.76 ? 54.07;
P , 0.05)].
During the follow-up, new diagnosed AF was documented on ECG
in five patients. In three of them AF was asymptomatic and was
detected in a routinary check-up, in one patient after a syncope
episode and in the other patient after a stroke. In all these patients
AF was correctly identified and registered as AHRE in the CIED.
Population ageing and broader indications are the main reasons for
the continuous increase in the use of PM, ICD, and CRT devices in
the USA and Europe.11,12 On the other hand, an increasing aged
population with underlying heart disease and the improvement of
diagnosis techniques have led to report a high prevalence of AF in
those over 70 years old.1 Therefore, patients receiving CIED share
co-morbidities (age, cardiovascular risk factors, heart disease, etc.)
associated also to an increased rate for AF.
Atrial fibrillation presents a two-fold mortality risk and a
fourto five-fold risk for stroke.2 It is usually recognized by the onset of
symptoms such as palpitations, dysponea, etc. However, in at least
one-third of patients, AF is associated with no obvious symptoms.
As a result, the initial manifestation of this ?silent? AF could be a
stroke or systemic embolism.3 It is not uncommon that AF is found
incidentally on admission for cerebral infarct. About 25 ? 30% of
patients presenting with strokes present AF that was not previously
recognized. Magnetic resonance imaging studies revealed that up to
40% of patients with AF had one or many silent cerebral infarcts.6
Improvements in prevention and early diagnosis techniques are
needed to identify these episodes of paroxysmal AF, even in the
absence of symptoms.
Today?s CIED diagnostics accurately detects AHRE when the atrial
rate exceeds the programmed arrhythmia detection rate during a
programmable number of beats. A critical issue is validating these
AHRE as AF. Multiple studies have reported that AHRE . 200 ?
250 b.p.m. and .5 min in duration had a high correlation with
atrial tachyarrhythmias validated by simultaneous stored intracardiac
electrograms.13,14 But even more important is to assess the clinical
significance of these episodes. In the Atrial Diagnostics Ancillary
Study of the MOde Selection Trial (MOST), patients with at least
one AHRE exceeding 5 min were more likely to have adverse clinical
outcomes, including a higher incidence of stroke, death, and
subsequent AF than were patients without AHRE.8 TRENDS was a
prospective, observational study enrolling 2486 patients with ?1
stroke risk factor (heart failure, hypertension, age ?65 years,
diabetes, or prior thrombo-embolic event) receiving PM or ICD that
monitor atrial tachycardia (AT)/AF burden (defined as the longest
total AT/AF duration on any given day during the prior 30-day
period). An AT/AF burden ?5.5 h on any given day during the
antecedent 30 days appeared to confer a doubling of thrombo-embolic
risk.9 Finally, results of the Asymptomatic AF and Stroke Evaluation
in Pacemaker Patients and the AF Reduction Atrial Pacing Trial
(ASSERT) showed that, in this population of PM patients with
hypertension but no history of AF nor anticoagulation, episodes of
devicedetected AT.6 min were found in approximately one-third over
almost 3 years of mean follow-up. Furthermore, these arrhythmias
were associated with a 2.5-fold increase in the risk of ischaemic
stroke and systemic embolism.10 Data from the ASSERT and
TRENDS studies are supported by several smaller, prospective
trials that have also examined the relationship between AHRE and
embolic events. In the study by Capucci et al.,15 AHRE lasting
.5 min did not increase embolic risk, while episodes lasting .24 h
did (OR 3.1). All these trials have shown AHRE to be an independent
predictor of thromboembolism, including ischaemic stroke.
Furthermore, there was a clear difference in embolic risk that became
apparent only when AHRE duration exceeded certain thresholds. Future
studies will be required to identify certain high-risk patients on the
basis of an AHRE duration threshold as well as the presence of
individual risk factors.
The development of sophisticated brain-imaging techniques,
initially with CT and subsequently with MRI, has shown that vascular
disease manifesting as infarcts can result in injury to the brain in the
absence of symptoms.16 Silent cerebral infarcts are frequently seen
in asymptomatic patients with AF.17 Recent studies have shown
that cortical/subcortical and deep white matter silent cerebral
infarcts are more frequent in non-valvular AF patients compared
with control subjects and CHADS2 score was an effective scheme
not only in stroke risk but also in risk of silent cerebral infarct.18
Moreover, brief episodes of subclinical AF (,48 h) documented by Holter
monitoring have been associated with a significantly increased risk of
silent cerebral infarct and stroke.19
Our data show that a high proportion of patients with CIED (25%
at 12 months) present AHRE . 5 min during the follow-up,
especially in those with previous AF (50% at 12 months) but also in a high
proportion of patients where AF has not yet been documented (19%).
The presence of AHRE was associated to a higher incidence (42 vs.
19%) of silent IBL on CT scan. Apart from age, hypertension and
small-vessel disease are the most widely accepted risks factors
strongly associated with silent brain infarcts in most studies.16 Our
findings were consistent with all these studies showing an increased
risk of silent IBLs on CT scan in older patients, in patients with higher
CHADS2 and CHA2DS2VASc scores, patients with previous AF or
prior stroke/TIA etc. But our data also showed that the presence
of AHRE . 5 min in this selected population of patients with CIED
was an independent risk factor associated to silent IBL detected on
CT scan, both in overall population (OR 3.04) and in patients
without prior history of AF or stroke/TIA (OR 5.83).
Silent AF has the same poor prognostic impact as symptomatic AF.
Atrial high rate episodes represent a kind of silent AF where
management recommendations are lacking despite the fact that a higher
embolic risk is present. Recently, 2014 AHA/ACC/HRS Guideline
for the management of patients with AF has point out the relevant
role of CIED in the diagnosis of silent AF but authors conclude that
further studies are needed to clarify the relation of AHRE and
stroke before providing treatment recommendations.20 Our findings
support to consider these AHRE as documented episodes of AF and
to evaluate different management alternatives regarding the
individual?s risk of stroke and thromboembolism of these patients. The
routinary application of anticoagulation therapy is as yet unclear
and challenging in the absence of randomized studies. To date, the
only prospective, randomized trial to address this question was the
IMPACT study, which was stopped prematurely and not published.21
Further studies are needed to establish the role of anticoagulation in
these patients. In this aspect, the recently designed ARTESIA study
will determine if treatment with apixaban, compared with aspirin,
will reduce the risk of ischaemic stroke and systemic embolism in
PM patients with subclinical AF and additional risk factors for
stroke.22 Future guidelines should also deal with this peculiar AF
scenario to make professionals that routinely perform CIED
followups aware of these relevant episodes but also to provide highly
The present study has the limitations associated to observational
single-centre studies. On the other hand, the study includes a ?real
life? highly reproducible PM population where an exhaustive
evaluation of the CIED diagnostic data have been performed, without
interfering in other settings of the devices attending to the clinical
characteristics of the patients, and where brain CT scan has been
obtained and blindly analysed. Due to the relatively small population
analysed, our results should be corroborated in future studies.
Only St Jude Medical devices were included in our study to
homogenize the parameters programmed and the detection algorithms
that could be different in devices from other companies. On the
other hand, our results are translatable to the great majority of
CIEDs that use similar detection criteria.
Sensitivity for infarct detection is better for MRI compared with
CT, particularly for small lesions located in the basal ganglia.
Studies using CT scan to detect silent brain infarcts will, therefore,
most probably report lower frequencies than those using a more
sensitive technique for small lesions as MRI. Therefore our data regarding
the thrombo-embolic risk associated to AHRE could be
underestimated. This aspect makes our results more clinically relevant and
more demanding for management recommendations.
Cardiac implantable electronic device can accurately detect AHRE
compatible with silent AF. These AHRE are really prevalent in
patients receiving dual-chamber devices, especially in those with
previously documented AF, but also in those patients with no history of
AF. The presence of AHRE has been associated to a high risk of stroke
and systemic embolism but our data also show that these patients
present a higher incidence of silent IBL on CT scan. Atrial high rate
episodes represent a kind of silent AF where management
recommendations are lacking despite the fact that a higher embolic risk
Conflict of interest: none declared.
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