Canadian Journal of Cardiology 37 (2021) 284e291

Clinical Research
Syncope in Patients With Severe Aortic Stenosis: More Than
Just an Obstruction Issue
Jaume Francisco-Pascual, MD,a,d,e Eduard Rodenas, MD,b,d Yassin Belahnech, MD,b,d
Nuria Rivas-Gándara, MD, PhD,a,d,e Jordi Perez-Rodon, MD, PhD,a,d,e
Alba Santos-Ortega, MD,a,d,e Begoña Benito, MD, PhD,a,d,e Ivo Roca-Luque, MD, PhD,a,d,e
Yolima Cossio-Gil, MD,c,d Vicens Serra Garcia, MD,b,d,e Sandra Llerena-Butron, MD,a
Julian Rodríguez-García, MD, PhD,a Angel Moya-Mitjans, MD, PhD, FESC,a,d,e
David García-Dorado, MD, PhD, FESC,b,d,e and Ignacio Ferreira-González, MD, PhD, FESCb,d,f
a
Unitat d’Arritmies. Servei de Cardiologia, Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca, Barcelona, Spain
b
Servei de Cardiologia, Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca, Barcelona, Spain
c
Unitat d’innovació i gestió de la informació, Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca, Barcelona, Spain
d
Universitat Autònoma de Barcelona, Bellaterra, Spain
e
Centro de Investigación Biome dica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain
f
Centro de Investigación Biome dica en Red de Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain

ABSTRACT 
RESUM 
E
Background: Severe aortic stenosis (AoS) is considered a primary nose aortique (SA) grave est la cause principale
Introduction : La ste
cause of syncope. However, other mechanisms may be present in de la syncope. Toutefois, comme d’autres me canismes peuvent être
these patients and accurate diagnosis can have important clinical presents chez ces patients, le diagnostic pre cis peut avoir des
implications. The aim of this study is to assess the different etiologies percussions cliniques importantes. Le but de la pre
re sente e
tude est
of syncope in patients with severe AoS and the impact on prognosis of valuer les diffe
d’e rentes e
tiologies de la syncope chez les patients
attaining a certain or highly probable diagnosis for the syncope. atteints d’une SA grave et les re percussions sur le pronostic pour
Methods: Out of a cohort of 331 patients with AoS and syncope, 61 parvenir à un diagnostic certain ou fortement probable de syncope.
had severe AoS and were included in the study. Main cause of syncope Me thodes : Parmi la cohorte de 331 patients atteints de SA et de
and adverse cardiac events were assessed. syncope, 61 patients qui avaient une SA grave ont e te
 inclus dans

Alongside dyspnea and angina, syncope is one of the classic when there is an increase in peripheral demand, mainly during
cardinal symptoms of severe aortic stenosis (AoS).1-3 In this physical exertion.1,3,4 Currently, clinical guidelines suggest
context, it tends to be attributed to transitory cerebral hypo- that the finding of severe AoS is the likely cause of the syn-
perfusion secondary to the incapacity to increase cardiac cope, particularly when there is no other obvious cause.2,5
output, owing to the obstruction caused by the valve disease, However, only a few papers in the literature have actually
examined the main causes of syncope in these patients.4,6,7
Received for publication February 23, 2020. Accepted April 28, 2020.
AoS causes not only obstruction of the left ventricular
outflow tract, but also morphologic and functional changes in
Corresponding authors: Dr Jaume Francisco-Pascual, Servei de Car-
diologia. Hospital Universitari Vall d’Hebron, Passeig de la Vall Hebron 119-
the myocardium8 and conductive tissue,9,10 as well as in
129, 08035 Barcelona, Spain. Tel.: (þ34) 934 893 000. autonomic control mechanisms,7,11 all of which can predis-
E-mail: [email protected] pose the patient to syncope due to other mechanisms. In
Dr Nuria Rivas-Gándara, Servei de Cardiologia. Hospital Universitari Vall addition to the potential mechanisms associated with the
d’Hebron, Passeig de la Vall Hebron 119-129, 08035 Barcelona, Spain. Tel.: senescence that currently characterizes patients with AoS,12
(þ34) 934 893 000.
E-mail: [email protected] recent investigations have shown that patients with severe
See page 291 for disclosure information. AoS and syncope have a different pathophysiologic phenotype

https://doi.org/10.1016/j.cjca.2020.04.047
0828-282X/Ó 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
Francisco-Pascual et al. 285
Syncope in Patients with Severe Aortic Stenosis

Results: In 40 patients (65.6%), we reached a certain or highly tude. Nous avons e

l’e value la cause principale de syncope et les
probable diagnosis of the main cause of the syncope. AoS was ve
e nements cardiaques inde sirables.
considered the primary cause of the syncope in only 7 patients (17.5% Resultats : Chez 40 patients (65,6 %), nous sommes parvenus à un
of the patients with known etiology). Atrioventricular block (14 diagnostic certain ou fortement probable de la cause principale de la
patients, 35.0%) and vasovagal syncope (6 patients, 15.0%) were the syncope. La SA e tait considere
e comme la cause principale de la
most frequently diagnosed causes. The presence of a known cause for syncope chez 7 patients seulement (17,5 % des patients d’e tiologie
syncope during the admission was not associated with a lower inci- connue). Le bloc atrioventriculaire (14 patients, 35,0 %) et la syncope
dence of recurrence during follow-up (hazard ratio [HR] 0.69, 95% vasovagale (6 patients, 15,0 %) e taient les causes les plus fre quem-
confidence interval [CI] 0.20-2.40). Syncope of unknown etiology was ment diagnostique es. La pre
sence d’une cause connue de syncope lors
independently associated with greater mortality during 1-year follow- de l’admission n’e tait pas associe e à une re cidive moins fre quente
up (HR 5.4, 95% CI 1.3-21.6) and 3-year follow-up (HR 3.5, 95% CI durant le suivi (rapport de risque [RR] 0,69, intervalle de confiance [IC]
1.2-10.3). à 95 % 0,20-2,40). La syncope d’e tiologie inconnue e tait associee de
Conclusions: In a high proportion of patients with severe AoS admitted façon independante à une mortalite  plus grande durant le suivi de 1 an
for syncope, the valvulopathy was not the main cause of the syncope. (RR 5,4, IC à 95 % 1,3-21,6) et le suivi de 3 ans (RR 3,5, IC à 95 % 1,2-
Syncope in two-thirds of this population was caused by either bra- 10,3).
dyarrhythmia or reflex causes. Syncope of unknown cause was asso- Conclusions : Pour une forte proportion de patients atteints de SA
ciated with increased short- and medium-term mortality, grave admis en raison d’une syncope, la valvulopathie n’e tait pas la
independently from treatment of the valve disease. An exhaustive cause principale de la syncope. La syncope des deux tiers de cette
work-up should be conducted to determine the main cause for population etait cause e soit par une bradyarythmie ou des causes
syncope. flexes. La syncope de cause inconnue e
re tait associe
e à une mortalite 
accrue à court ou à moyen terme, inde pendamment du traitement de
la valvulopathie. Un bilan exhaustif devrait être realise
 pour determiner
la cause principale de syncope.

from patients operated on for other symptoms, and that they electrophysiologic study and prolonged monitoring, were
might have a worse prognosis after valve replacement.8 performed in line with the clinician’s judgment according to
Considering the complexity of these patients’ cardiopathy, the suspected diagnosis and applicable recommendations. In
we hypothesized that in a high proportion of patients the all patients, indication for valve replacement was considered
syncope is mainly due to a different cause distinct from the and discussed with both the heart team and the patient to
actual obstruction caused by the valvulopathy (which could be reach a final decision. In addition, if the patient had a different
an aggravating or predisposing factor or, in some cases, a cause for the syncope, this was treated appropriately according
simple bystander) and that appropriate diagnosis may have to clinical practice guidelines,2 eg, pacemaker implantation for
prognostic implications. atrioventricular (AV) block, lifestyle recommendations in pa-
The aim of the present study was to assess the various tients with vasovagal syncope, modification of hypotensive
causes of syncope in patients with severe AoS and the prog- medications, etc. After being discharged from hospital,
nostic impact of having a certain or highly probably diagnosis patients were followed as cardiology outpatients.
of the syncope. The study complied with the Helsinki declaration and was
approved by the local ethics committee.

Methods Definitions
Study population The severity of the AoS was determined by means of
echocardiography in line with ESC clinical guidelines.3
We carried out a single-center cohort study including all We established the main cause of the syncope as certain or
consecutive patients from January 2010 to August 2018 with highly probable according to the definitions present in the
syncope and severe AoS at the time of the syncopal episode European Society of Cardiology (ESC) guidelines on syn-
admitted to a tertiary university hospital that is a reference cope2,13 (Table 1). The patient details were analysed on an ad
center for cardiac surgery and arrhythmias (Hospital Uni- hoc basis by 2 nonblinded cardiologists specialized in syncope
versitari Vall d’Hebron, Barcelona, Spain). In February 2019, to establish a definitive diagnosis in line with those definitions.
we collected the final follow-up data for the patients. Each The causes of recurrences of syncope were defined in the same
patient’s clinical details, the characteristics of the syncope, its manner.
management, and follow-up were obtained from the
electronic medical records of the center.
Statistical analysis
The patients were systematically assessed and managed in
line with applicable European Society of Cardiology (ESC) The categoric variables are presented as an n (%). The
guidelines for syncope2,13 and valvulopathies.3 The patients continuous quantitative variables are presented as median
were admitted to hospital with telemetry electrocardiographic (interquartile range [IQR]).
monitoring for a minimum of 48 hours. We took a clinical Comparison of the numeric variables was performed with
history and performed a targeted physical examination the use of the Student t test or the Wilcoxon rank sum test,
including a test for orthostatic hypotension and a trans- depending on the distribution of the variables. The chi-square
thoracic echocardiogram. Other complementary tests, such as test or Fisher exact test was used to compare qualitative
286 Canadian Journal of Cardiology
Volume 37 2021

Table 1. Definitions of the causes of the syncope

Syncope diagnosis Definition
Vasovagal syncope Certain Precipitated by emotional distress or orthostatic stress and associated with a typical prodrome
Highly probable Associated with typical prodrome but without any clear trigger, or associated with typical trigger
with minimal prodrome
Carotid sinus hypersensitivity Certain Syncope is reproduced in the presence of asystole > 3 seg and/or fall in systolic BP > 50 mm Hg
during CSM
Highly probable Presence of asystole > 3 seg and/or fall in systolic BP > 50 mm Hg during CSM without
reproducing the syncope
Orthostatic syncope Certain Occurs after standing up and there is documentation of symptomatic OH in active standing test
Highly probable Occurs after standing up and there is documentation of asymptomatic OH in active standing test
Arrhythmic syncope Certain Clear correlation with an arrhythmic event and syncope, or diagnostic findings in the EPS: HV
interval > 70 ms, advanced AV block, induction of VT or SVT that reproduces the symptoms,
or SNRTc > 525 ms
Highly probable Documentation of asymptomatic advanced AV block, asystole > 3 seg, SVT, or VT
Exercise low cardiac output Highly probable Occurs during intense exercise, such as fast walking, running, or dancing, without criteria for
previous diagnosis
Acute coronary syndrome Highly probable Occurs during the acute phase of an ACS, with typical chest pain, acute ischemic ECG changes,
and/or elevation of troponin
ACS, acute coronary syndrome; AV, atrioventricular; BP, blood pressure; CSM, carotid sinus massage; ECG, electrocardiographic; EPS, electrophysiologic
study; HV, His bundleeventricular; OH, orthostatic hypotension; SNRTc, corrected sinus node recovery time; SVT, supraventricular tachycardia; VT, ventricular
tachycardia.

variables, as appropriate. Missing values were not included in supraventricular tachycardia, in 1 patient it was due to
the analysis. The survival functions were estimated with the carotid sinus hypersensitivity, and in 1 patient it occurred in
use of the Kaplan-Meier method. A Cox multivariate pro- the context of an acute coronary syndrome. Table 3 sum-
portional hazard model was created to predict short-term (1 marizes the etiologic diagnosis of syncope, the degree of cer-
year) and medium-term (3 years) survival, with the use of all tainty of the diagnosis, and the key data used to reach the
the statistically significant variables in the univariate analysis diagnosis.
to identify predictive factors independent of mortality. A P
value of < 0.05 was considered to be statistically significant
Clinical follow-up, recurrence of syncope, and short- and
for all of the analyses. The statistical analyses were performed
medium-term prognosis
with the use of Stata, version 15.1.0 (StataCorp, College
Station, TX). The median follow-up period was 31.0 months (IQR
11.8-59.8 months). One patient was lost to follow-up.
Forty-three (70.5%) of the patients received an aortic valve
Results replacement (AVR: 18 (29.5%) surgical with tissue valve
Baseline characteristics replacement, 6 (9.8%) with mechanical valve replacement,
and 19 (31.2%) via transcatheter aortic valve implantation.
During the study period, 336 patients with some degree of Eighteen patients (29.5%) were treated with conservative
AoS and syncope were admitted. In 61 of them, the medical management owing to severe comorbidities or the
valvulopathy was considered to be severe at the time of the patient’s own wishes. Within this group, a palliative
syncopal episode and they were included in the analysis
(Fig. 1). Table 2 summarizes the baseline characteristics of the
patients. The median age of the patients at the time of
syncope was 81.2 years (IQR 75.6-85.5 years) and 44.3%
were female; 81.2% were on some form of antihypertensive
treatment. The median LVEF was 58% (IQR 54%-64%) and
the median mean gradient was 53 mm Hg (IQR 44-65 mm
Hg). Seven (11.5% ) of the syncopal episodes occurred during
intense physical exercise.
Etiology of the syncope
We obtained a certain or highly probable diagnosis of the
main cause of the syncope in 40 patients (65.6%; Fig. 2). In
only 7 patients (17.5% of the patients with a known cause),
the severe AoS was considered to be the main cause of the
syncope due to low cardiac output during exercise. In 14
patients (35.0%), the main cause of the syncope was complete
or advanced AV block, in 6 patients (15.0%) it was vasovagal
in origin, in 5 patients (12.5%) it was due to sinus node
dysfunction, in 4 patients (10.0%) it was due to orthostatic Figure 1. Flow chart of the patients included in the study. AoS, aortic
hypotension, in 2 patients (5.0%) it was due to a stenosis.
Francisco-Pascual et al. 287
Syncope in Patients with Severe Aortic Stenosis

Table 2. Characteristics of the patients included in the study

Unknown cause of Known cause of
Variable Total (n ¼ 61) syncope (n ¼ 21) syncope (n ¼ 40) P value
Age, y 81.2 (75.6-85.5) 84.4 (80.2-87.3) 81.4 (74.4-84.3) 0.0272
Female 44.3% (27) 52.4% (11) 40.0% (16) 0.355
Active smoking 19.7% (12) 19.1% (4) 20.0% (8) 0.609
Dyslipidemia 72.1% (44) 66.7% (14) 75.0% (30) 0.490
Hypertension 80.3% (49) 85.7% (18) 77.5% (31) 0.443
Diabetes 36.1% (22) 33.3% (7) 37.5% (15) 0.747
Ischemic heart disease 24.6% (15) 28.6% (6) 22.5% (9) 0.601
Previous myocardial infarction 9.9% (6) 9.5% (2) 10.0% (4) 1
Previous valve replacement 1.64% (1) 0% (0) 2.5% (1) 1
Pacemaker/implantable cardioverter- 4.9% (3) 4.76% (1) 5.0% (2) 1
defibrillator
Previous syncope 9.8% (6) 9.5% (2) 10.0% (4) 1
Atrial fibrillation 24.6% (15) 23.8% (5) 25.0% (10) 0.308
Pharmacologic therapy
ACE-I/ARB 58.3% (35) 71.4% (15) 51.3% (20) 0.131
Beta-blocker 26.7% (16) 23.8% (5) 28.2% (11) 0.713
Calcium channel blocker 16.67% (10) 23.8% (5) 12.8% (5) 0.276
Alpha-blocker 13.3% (8) 9.5% (2) 15.4% (6) 0.701
Thiazide 33.3% (20 ) 23.8% (5) 38.4% (15) 0.251
Furosemide 28.3% (17) 33.3% (7) 25.6% (10) 0.528
Spironolactone 5.0% (3) 4.8% (1) 5.1% (2) 1
Psychoactive drug 23.3% (14) 14.3% (3) 28.2% (11) 0.340
Nitrate 3.3% (2) 9.5% (2) 0% (0) 0.119
Any diuretic 59.0% (36) 61.9% (13) 57.5% (23) 0.740
Any antihypertensive 81.2% (49) 85.7% (18) 79.5% (31) 0.552
Characteristics of the syncope
Prodrome 33.3% (20) 38.1% (8) 30.7% (12) 0.566
Presence of trigger 37.9 (22) 15.0% (3) 50.0% (19) 0.011
Severe trauma 35.1% (20) 35.0% (7) 35.1% (13) 0.992
Standing/slow walking 75.9% (44) 95.0% (19) 68.4% (25) 0.021
Sitting 10.3% (6) 5.0% (1) 13.1% (5) 0.653
Intense exercise 12.1% (7) 0% (0) 18.4% (7) 0.083
Echocardiography
TSD (mm) 28 (24-35) 27 (22-25) 30 (25-35) 0.2969
TDD (mm) 44 (42-50) 44 (42-47) 44 (42-51) 0.5247
Septum (mm) 15 (14-16) 15.5 (14-16.5) 15 (13-16) 0.2356
PAPs (mm Hg) 33 (28-44) 32 (30-45) 34 (26-43) 0.8303
LVEF (%) 58 (54-64) 62 (55.7-65) 57 (50.5-60) 0.0465
AR þþþ/þþþþ 13.56% (8) 4.76% (1) 18.42% (7) 0.142
MR þþþ/þþþþ 15.52% (9) 14.29% (3) 16.22% (6) 0.581
Ao maxG (mm Hg) 81 (68-96) 89 (72.5-100.5) 80 (65-91) 0.0429
Ao meanG (mm Hg) 53 (44-65) 59 (45-66) 52.5 (43-58.5) 0.2331
Values are presented as median (interquartile range) or % (n).
ACE-I, angiotensin-converting enzyme inhibitor; Ao, aortic; AR, aortic regurgitation; ARB, angiotensin receptor blocker; G, gradient; LVEF, left ventricular
ejection fraction; MR, mitral regurgitation; PAPs, systolic pulmonary artery pressure; TDD, telediastolic diameter; TSD, telesistolic diameter.

valvuloplasty was performed in 4 patients. Seventeen A total of 21 patients (34.4%) died, 3 during the initial
definitive pacemakers and 2 resynchronization devices with hospital admission and the rest during follow-up. Eleven
pacemaker were implanted to treat the syncope. In addition, 5 patients (52.4% of those who died) died due to non-
patients required a definitive pacemaker owing to iatrogenic cardiovascular causes, 7 (33.3%) due to cardiovascular causes,
AV block after AVR. and 4 (19.0%) suddenly. Figure 4 summarizes the causes of
Figure 3 summarizes the recurrences of syncope observed death in patients undergoing AVR. Those patients who died
during follow-up. Thirteen patients (21.3%) had a further did not show significant differences regarding baseline char-
syncopal episode (7 of which occurred in patients after AVR). acteristics except for a slightly greater median age (80.1 [IQR
Patients undergoing AVR had a lower incidence of recurrence 74.4-84.3] years vs 84.4 [IQR 80.9-88.9] years; P ¼ 0.01;
of syncope in the medium term (hazard ratio [HR] 0.27, 95% Supplemental Table S1). The patients who did not undergo
confidence interval [CI] 0.08-0.94). Syncope of known cause AVR had a greater mortality rate in the medium term (3
was not associated with a lower incidence of recurrence years; HR 6.9, 95% CI 2.4-20.2). There were no significant
during follow-up (HR 0.69, 95% CI 0.20-2.40) differences related to the type of valve replacement.
(Supplemental Fig. S1). Nine patients with a known cause for In the multivariate analysis, after adjusting for age and the
the index syncope had a recurrent syncopal event, and a presence of valve replacement, the absence of an etiologic
different cause was found in 7 of these patients. One patient diagnosis for the syncopal episode was independently associ-
with sinus node dysfunction who rejected pacemaker ated with greater mortality during short-term follow-up (1
implantation after the index event had a recurrence due to the year; HR 5.4, 95% CI 1.3-21.6) and medium-term follow-up
same cause. (3 years; HR 3.5, 95% CI 1.2-10.3; Table 4). Figure 5 shows
288 Canadian Journal of Cardiology
Volume 37 2021

Figure 2. Etiologic diagnosis of syncope in patients with severe AoS. AV block, advanced atrioventricular block; LCO, low cardiac output; OH,
orthostatic hypotension; SND, sinus node disfunction; SVT, supraventricular tachycardia.

the Kaplan-Meier curves adjusted for age, the presence of in 5%-25% of these patients.7,8,14,15 Traditionally, this
valve replacement, and the presence or absence of an etiologic symptom is attributed to a reduction in cerebral flow due to
diagnosis of the syncope. incapacity to increase cardiac output when vasodilation of
muscular arteries occurs during exercise, thus producing a
drop in blood pressure. In an early paper by Hammarsten,1 in
Discussion 14 (87.5%) of 16 patients with severe AoS, the syncope
To our knowledge, this is the largest contemporary series occurred during intense exercise. However, the baseline
and the first to analyse the main cause of the syncope and its characteristics of those patients were distinct from those of
relevance to the prognosis of patients with AoS. This paper patients with severe AoS today. In the present study, only 7
offers 2 significant main findings. The first is the high patients (11.5%) had a loss of consciousness clearly related to
percentage of alternate causes for syncope other than the moderate or intense physical exercise and thus attributable to
obstruction caused by AoS. The second is the fact that this mechanism. In the rest of the cases, syncope occurred at
performing an etiologic diagnosis of the syncope has major rest or during low-intensity physical activity similar to that
prognostic implications for mortality in both the short and the carried out on a daily basis, which suggests that there are other
medium terms. causes to explain the syncope.
AoS is currently the most common acquired valvulopathy Today, patients with severe AoS are elderly (median age
in developed countries. In published series, syncope is present 81.2 years in the present series) with a high prevalence of

Table 3. Etiologic diagnosis of syncope: degree of certainty of the diagnosis and key data used to reach the diagnosis, n (%)
Main cause* Total of diagnosis Certain Highly probable Key datay
AV block 14 6 (42.9%) 8 (57.1%) ECG on admission: 4
EPS (HV interval > 70 ms): 5
Telemetry on admission: 4
Prolonged ECG monitoring during admission: 1
Exercise LCO 7 0 7 (100%) Clinical criteria: 7
Vasovagal 6 1 (16.7%) 5 (83.3%) Clinical criteria: 6
SND 5 3 (60.0%) 2 (20.0%) Telemetry on admission: 4
Prolonged ECG monitoring during admission: 1
OH 4 0 4 (100%) Clinical and physical exploration criteria: 4
SVT 2 1 (50.0%) 1 (50.0%) ECG on admission: 1
EPS (SVT induction with hypotension): 1
CSH 1 1 (100%) 0 Clinical and physical exploration criteria: 1
ACS 1 0 1 (100%) ECG on admission and clinical criteria: 1
ACS, acute coronary syndrome; AV block, advanced atrioventricular block; CSH, carotid sinus hypersensitivity syndrome; ECG, electrocardiographic; EPS,
electrophysiologic study; HV, His bundleeventricular; LCO, low cardiac output; OH, orthostatic hypotension; SND, sinus node dysfunction; SVT, supraven-
tricular tachycardia.
* Main etiology of the syncope and the degree of certainty of the diagnosis were established according to the definitions present in the European Society of
Cardiology (ESC) guidelines on syncope2,13 (Table 1).
y
Key data summarize the explorations and/or clinical findings that were fundamental to establish the diagnosis according to the previous established definitions.
Francisco-Pascual et al. 289
Syncope in Patients with Severe Aortic Stenosis

Figure 3. Causes of syncope recurrences. Schema showing the cause of the index syncope and that of the recurrence in the 13 patients who had a
recurrence of syncope. Each arrow represents a patient with recurrence of syncope. We differentiate between the patients having undergone aortic
valve replacement and those who did not. AV block, advanced atrioventricular block; LCO, low cardiac output; OH, orthostatic hypotension; SND,
sinus node disfunction; SVT, supraventricular tachycardia.

cardiovascular risk factors, comorbidities, and multiple phar- block, 12.5% sinus node dysfunction), reflex syncope, and
macologic therapies. As such, a high prevalence of conduction orthostatic hypotension. These results corroborate the
disorders and arrhythmias has been described in patients with possible pathophysiologic mechanisms discussed above.
AoS,9,10,16 as well as a greater susceptibility to vasovagal reflex However, it is important to note that, although there is an
and orthostatic hypotension,7,11,15 all of which are factors able alternate main cause for the syncope, AoS may play a key role
to cause or promote syncope. in its genesis, promoting or aggravating the hemodynamic
In the present study, by assessing patients with syncope in response. In this regard, it should be noted that patients with
a manner similar to that used for patients without AoS, we syncope of unknown cause had a maximal aortic gradient
were able to reach a high rate of certain or highly probable significantly greater than the patients with syncope of known
diagnoses (in 65.6% of the patients). It is noteworthy that in cause, which may suggest that in patients with critical AoS,
82.5% of these patients a main cause different from obstruction per se may play a more important role in the
obstruction due to AoS was found. The most frequently pathophysiology.
diagnosed causes were bradyarrhythmia (35% advanced AV During follow-up, 13 patients (21.3%) had a recurrence of
syncope. This proportion of recurrence is similar to that
described in the literature. Wilmshurst et al.6 published a
series of 39 patients with syncope who underwent AVR. In 26
of them, syncope was related to exertion and in the rest it was
not. Among them, only patients with noneexertion-related
syncope (8 patients, 30.8%) had a recurrence of syncope after
AVR. In our series, patients who had AVR had a lower risk of
syncope recurrence independently from the cause of the
syncope, which supports the theory that the obstruction
contributes to the genesis of the syncope. In contrast, the fact
that an etiologic diagnosis for the syncope was obtained was
not associated with a reduction in recurrence. This observa-
tion may be due to several mechanisms. One is the fact that,
in some patients, apart from the main cause of syncope, other
Figure 4. Causes of mortality during follow-up of patients undergoing mechanisms coexist, in particular, a greater vasovagal
aortic valve replacement. susceptibility. This concept of multifactorial mechanisms is
290 Canadian Journal of Cardiology
Volume 37 2021

Table 4. Independent predictors of mortality

Short term (1 year) Medium term (3 years)
Predictor HR (95% CI) P value HR (95% CI) P value
Absence of valve replacement 2.9 (0.7-11.5) 0.135 6.5 (1.9-22.1) 0.003
Syncope of unknown cause 5.4 (1.3-21.6) 0.018 3.5 (1.2-10.3) 0.019
Multivariate Cox regression analysis assessing the impact of aortic valve replacement and etiologic diagnosis of syncope on 1-year (short-term) and 3-year
(medium-term) mortality.
CI, confidence interval; HR, hazard ratio.

consistent with current guidelines.2,5 Another is the fact that, according to their prior symptoms. Of 625 patients, 67 had
in a high proportion of patients, the recurrence had a different had 1 or more episodes of syncope before the procedure.
cause than the initial episode, as shown in Figure 2. This These patients had a greater risk of mortality after AVR in
phenomenon is not unusual and is described in the both the short term (HR 2.27, 95% CI 1.04-4.95) and the
literature.12,17-19 long term (HR 2.11, 95% CI 1.39-3.21) compared with
One of the present study’s key findings concerns the patients who did not have syncope. Although patients with
prognostic implications regarding mortality of reaching syncope had somewhat different characteristics on echocar-
(or not reaching) an etiologic diagnosis of the syncope. diography (smaller aortic valve area, smaller cardiac cham-
Independently, those patients in whom it was not possible to bers, and lower ejection volumes), we think that this rise in
precisely determine the cause of the syncope had more than mortality was also partially due to the presence of other
triple the short- and medium-term mortality. Although the causes for the syncope, such as underdiagnosed
sample size is limited, it is striking that sudden death and arrhythmias.20,21
cardiovascular death after AVR was concentrated in this At present, clinical guidelines suggest the finding of severe
patient subgroup. This may be due to the fact that, in this AoS to be considered the likely cause of the syncope,
group of patients, there are potentially serious causes for the particularly if there is no other obvious cause.2,5 In light of the
syncope left untreated due to a lack of diagnosis. Specifically, present study, although the obstruction caused by AoS can be
bradyarrhythmia might be one of the main underdiagnosed a cause of syncope per se, we think it is necessary to perform an
etiologies according to the results of the study and the fact exhaustive and systematic investigation of other possible
that they respond very well to stimulation therapy. This causes without this modifying or delaying the indication
observation tallies with that made by Soteriades et al.20 in a for AVR.
patient cohort with syncope in the Framingham Heart
Study. Patients with syncope of unknown origin had an Limitations
increased risk of all-cause mortality compared with the This study has several limitations. First, it is an observa-
general population (HR 1.32, 95% CI 1.09-1.60), unlike tional study of a cohort with a limited number of patients, so
the patients with vasovagal syncope whose mortality was it may be subject to potential biases, although the patients
comparable with the general population. Recently, Goliasch were included consecutively and we performed an analysis for
et al.8 examined the prognosis of patients undergoing AVR possible confounding factors. On the other hand, the patients
were assessed in line with general clinical practice guidelines
and some investigations were performed according to the
judgment of the attending medical team. We did not have a
specific systematic protocol suited to this cardiopathy, which
we think could increase the diagnosis rate and modify the
prognosis.

Conclusion
In a high proportion of patients with severe AoS
admitted for syncope, the valvulopathy was not the main
cause of the syncope. Syncope in two-thirds of this
population was caused by either bradyarrhythmia or reflex
causes. Syncope of unknown cause was associated with
increased short- and medium-term mortality, indepen-
dently from treatment of the valve disease. An exhaustive
work-up should be conducted to determine the main
cause for syncope.
Figure 5. Survival analysis. Kaplan-Meier analysis adjusted for age
according to valve replacement and the etiologic diagnosis of the
syncope. Log-rank P ¼ 0.016 for events over 3 years of follow-up, Acknowledgements
comparing patients undergoing valve replacement with an etiologic The authors thank the Cardiology Epidemiology Unit of
diagnosis with those in whom no diagnosis was reached. AVR, aortic Vall d’Hebron Hospital for their support in statistical
valve replacement. analysis.
Francisco-Pascual et al. 291
Syncope in Patients with Severe Aortic Stenosis

Funding Sources 12. de Ruiter SC, Wold JFH, Germans T, Ruiter JH, Jansen RWMM.
This paper was funded by Instituto de Salud Carlos III, Multiple causes of syncope in the elderly: diagnostic outcomes of a Dutch
Fundació Marató TV3, Centro de Investigación Biomedica en multidisciplinary syncope pathway. Europace 2018;2:867-72.
Red, and the European Regional Development Fund.
13. Moya A, Sutton R, Ammirati F, et al. Guidelines for the diagnosis and
management of syncope (version 2009). Eur Heart J 2009;3:2631-71.
Disclosures
14. Omran H, Fehske W, Rabahieh R, et al. Valvular aortic stenosis: risk of
The authors have no conflicts of interest to disclose.
syncope. J Heart Valve Dis 1996;5:31-4.

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