Autonomic Parameter and Stress Profile Predict

Secondary Ischemic Events After Transient Ischemic

Attack or Minor Stroke
Ling Guan, MD, PhD; Yongjun Wang, MD; Victoria E. Claydon, PhD; Garey Mazowita, MD;
Yilong Wang, MD, PhD; Rollin Brant, PhD; Jean-Paul Collet, MD, PhD

Background and Purpose—Traditional risk factors for ischemic stroke are body stressors that are related to autonomic
autonomic system (ANS) dysfunction. The value of ABCD2 score (age, blood pressure, clinical features, duration
of symptoms, diabetes) to predict ischemic stroke after transient ischemic attack is compromised by the inclusion
of a limited number of stressors. We aimed to assess whether markers of ANS function and stress could predict the
occurrence of secondary ischemic events after transient ischemic attack or minor stroke.
Methods—This is a prospective cohort study in which 201 patients were recruited within 48 hours after initial transient
ischemic attack or minor stroke and followed for 90 days to assess the development of secondary ischemic events.
ABCD2 score, heart rate variability (HRV) parameters as markers of ANS function, and psychological stress were
assessed. Logistic regression and area under the curve (AUC) were used to assess the models’ predictive ability.
Results—Morning high frequency (HF) HRV power and changes in HF HRV from morning to afternoon (daytime HF
changes) were the most useful HRV predictors for both ischemic events (AUC=0.61 and 0.70) and ischemic stroke
(AUC=0.62 and 0.72). Compared with ABCD2 score, 2 HRV-based stress models showed higher predictive ability for
ischemic events (AUC=0.82 versus 0.63, 0.76 versus 0.63; P<0.05) and ischemic stroke (AUC=0.87 versus 0.64, 0.82
versus 0.64; P<0.05).
Conclusions—Assessing the effects of stress on the ANS may be an innovative way to stratify the risk of ischemic events
after transient ischemic attack or minor stroke. New risk stratification by assessing the dynamic features of ANS
dysfunction and stress may help identify high-risk sub-populations that may benefit from added management.   (Stroke.
2019;50:2007-2015. DOI: 10.1161/STROKEAHA.118.022844.)
Downloaded from http://ahajournals.org by on April 2, 2020

Key Words: autonomic nervous system ◼ ischemic attack, transient ◼ risk factors ◼ stress, psychological ◼ stroke

U p to 23% of strokes are preceded by a transient ischemic

attack (TIA) or minor stroke,1 suggesting that these 2
events are potentially predictive of future severe ischemic
stroke rather than benign events.2 Imaging assessment pro-
vides good predictive power for ischemic stroke, evidenced by
an area under the curve (AUC) higher than 0.83 and can help
guide medical treatment such as lipid-lowering therapy for ca-
rotid stenosis. However, it is costly and technique dependent;
perhaps most importantly, even with guideline-oriented
medical treatment, there remains a proportion (7%–12%)
of patients with recurring ischemic events after the initial
events.4 We consider that there may be a specific at-risk popu-
lation that would benefit from additional medical care that has
not generally been identified by imaging tests.
The predictive ability of the traditional ABCD2 score
(age, blood pressure, clinical features, duration of symptoms,
diabetes) for ischemic stroke ranges from AUC 0.55 to 0.7.5
This moderate predictive value may be a consequence of the
limited number of risk factors included in the assessment.
ABCD2 risk factors, and other identified risk factors such as
smoking and alcohol abuse, are all considered to be chronic
body stressors.6 Similarly, acute triggers of ischemic stroke
such as infections and psychological stress act as acute stress-
ors. Clearly, many risk factors, or stressors are poorly con-
sidered using current criteria, and it is likely that additional
important factors or stressors have yet to be identified.
Stress refers to a threatened state caused by any form of
internal or external disturbing force.7 Stress response refers to

Received November 20, 2018; final revision received May 7, 2019; accepted May 10, 2019.
From the Department of Medicine (L.G., J.-P.C.), BC Children’s Hospital Research Institute (L.G., J.-P.C.), Department of Family Practice (G.M.), and
Department of Statistics (R.B.), University of British Columbia, Vancouver, Canada; Department of Neurology, Beijing Tiantan Hospital, China (Yongjun
Wang, Yilong Wang); Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Canada (V.E.C.); Department of Family and
Community Medicine, Providence Healthcare, Canada (G.M.); and Advanced Innovation Center for Human Brain Protection, Beijing Tiantan Hospital,
Capital Medical University, China (J.-P.C.).
Presented in part at the International Stroke Conference, Los Angeles, CA, January 24–26, 2018.
The online-only Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.119.024914.
Correspondence to Jean-Paul Collet, MD, PhD, Room V3-320, 948 W 28th Ave, Vancouver, BC V6H 3N1. Email jcollet@bcchr.ca
© 2019 American Heart Association, Inc.
Stroke is available at https://www.ahajournals.org/journal/str DOI: 10.1161/STROKEAHA.118.022844

2007
 2008  Stroke  August 2019
a counteracting force to neutralize the effect of stressors and
re-establish homeostasis.7 The stress response is tightly regu-
lated by the autonomic nervous system (ANS).8,9 Frequent
exposure to chronic or acute stressors (sources of primary phys-
iological stress) make ANS adaptation to stress dysfunctional10
and provide a substrate for pathophysiological consequences
such as the development of atherosclerosis7 that themselves be-
come another source of physiological stress. Both primary and
secondary stresses, along with dysfunctional ANS responses,
ultimately contribute to the development of ischemic stroke.
Ischemic stroke, therefore, may be seen as the final end point
of the cumulative effects of multiple stressors.6,11
Assessing ANS function may capture the comprehensive
effects of both chronic stressors/risk factors and acute triggers
and thus help to identify the personalized risk of developing
secondary ischemic events after an initial TIA or minor stroke.
ANS activity can be measured by heart rate variability (HRV)
whose parameters represent the expression of both chronic and
acute stressors at the time of assessment.12 Changes in HRV
during a period may reflect a change in stress or a change in
ANS stress coping ability (ie, rebound capacity) during the
period.13 We aimed to assess whether frequency domain (Fast-
Fourier transformation) HRV-based markers of ANS function
and stress could predict the occurrence of secondary ischemic
events after initial TIA or minor stroke and compare HRV-based
stress models with ABCD2 score. We hypothesized that incor-
poration of ANS indicators and stress profiles would enhance
the prediction of ischemic events after TIA or minor stroke.
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Methods
This study was approved by the University of British Columbia Ethics
Board and Beijing Tiantan Hospital affiliated to Capital Medical
University Ethics Board. Study data cannot be made public because
patients did not give consent to share them at the time of recruitment.
Researchers interested by any aspect of data handling and analysis
should contact the corresponding author.
Study Design and Population
This was a prospective cohort study of patients who developed TIA or
minor stroke at Beijing Tiantan hospital.
Patients were eligible for the study if they were over 40 years old
and diagnosed with TIA or minor stroke. TIA was defined as a tran-
sient episode of neurological dysfunction caused by focal cerebral,
spinal cord, or retinal ischemia without permanent cerebral infarc-
tion.2 The preliminary diagnosis of TIA in the Emergency clinic was
made by a neurologist according to the time-based diagnosis criteria
(duration <24 hours)14; this initial diagnosis was revised in the wards
with imaging examinations according to tissue-based diagnosis cri-
teria.2 Minor stroke was defined as ischemic stroke with mild and
nondisabling symptoms. Patients with minor stroke had a total score
on the National Institutes Health Stroke Scale score of <4.15 Patients
with TIA or minor stroke were only eligible for the study if they pro-
vided consent within 48 hours of onset of the primary event. Patients
who had serious diseases such as cancer or frequent arrhythmia that
would influence HRV analysis such as permanent atrial fibrillation,
atrial flutter, or frequent premature beats, as well as those who could
not start the 24-hour Holter recording within 48 hours after the initial
event were excluded from the study.
Variable Assessment
Demographic and clinical information was noted (for definitions see
the online-only Data Supplement) including the following: age, sex,
current symptoms and duration, historical and present illnesses, atrial
fibrillation, hypertension, diabetes mellitus, dyslipidemia, cardiovas-
cular or cerebrovascular diseases, medication use, TOAST classifi-
cation (Trial of ORG 10172 in Acute Stroke Treatment), as well as
smoking habits and alcohol intake. This information was collected
from medical charts and patient self report.
The ABCD2 score was calculated for each study patient. It was
used either as continuous or categorical variables.16,17
All eligible patients received 24-hour Holter recording starting
between 8 and 9 am on the nearest morning after their enrollment.
Holter monitors were removed at 7 am the following morning. The
raw data from the 24-hour Holter were extracted for HRV analyses,
using Acqknowledge 4.1 software (BIOPAC Systems, Inc, Goleta,
CA). The main HRV frequency-domain parameters assessed in the
study were12 high-frequency (HF) power (millisecond [ms]2), which
predominantly reflects parasympathetic nervous system (PNS) reg-
ulation; normalized HF (normalized unit), which represents the rel-
ative value of HF in the context of other influences on HRV; HF and
low frequency combined (ms2), which is considered the fraction of
HRV that can be explained by autonomic modulation; and total power
(ms2) which is a sign of overall ANS activity.
For the purpose of analysis, we defined morning as the period
from 9 am to 12 pm; afternoon from 3 to 6 pm; and night from 12 to 3 am.
Definitions for the selected HRV parameters are described in Figure 1.
Study patients completed the validated 10-question Perceived
Stress Scale (PSS) at the earliest convenient time. The PSS is the
most widely used psychological instrument for measuring the degree
to which situations in one’s life in the last month are appraised as un-
predictable, uncontrollable, with overloaded perceived stress.18 The
maximal score for PSS is 40, with higher scores indicating higher
levels of perceived stress. Normal populations have PSS score lower
than 15; scores ≥20 are considered to reflect high stress.18
Outcome Measures
The primary study end point was the occurrence of any of the follow-
ing ischemic events: ischemic stroke, TIA, cardiovascular events, and
vascular death within 90 days after the initial TIA or minor stroke.
The secondary end point was the occurrence of ischemic stroke alone.
Standardized definitions of ischemic events were used.19
All study patients were followed for 90±5 days during which the
development of all symptoms relatable to ischemia and the occur-
rence time were recorded. The adjudication committee made of ex-
perienced neurologists reviewed all outcome events for validation.
Patients’ overall health condition and any change in their clinical
status was also recorded.
Statistical Analyses
Demographic and clinical characteristics were described as catego-
rical or continuous variables.
We used logistic regression modeling for the prediction anal-
ysis. Absolute values of HRV were log-transformed. Odds ratios for
changes in HRV were calculated to represent a change of risk for
every 10% change in HRV parameters during the defined time period.
Classification performance of the ABCD2 (as a reference), PSS, HRV
predictors, and HRV models were tested. Cutoff criteria were identi-
fied for selected HRV predictors and HRV models, based on high
sensitivity (90%) in predicting the end points.
Finally, we developed more complex exploratory stress models
(ESMs) with a combination of HRV absolute values, HRV changes,
ABCD2 score, and PSS score. The general rule of maximum Youden’s
index (sensitivity+specificity-1)20 was used to identify the cutoffs to
create the risk level in exploratory models.
A P value of <0.05 was used in significance testing. All statistical
analyses were conducted using R 3.3.2.
Results
Approximately 3000 patients with TIA or minor stroke were
screened in the Emergency clinic, from October 2014 to
 Guan et al   ANS and Stress in TIA and Minor Stroke   2009
Figure 1. Definitions of selected heart rate variability (HRV) parameters.
February 2016. Among them, 347 had developed the initial
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events within the past 48 hours. For various reasons, commenc-
ing the Holter within 48 hours was not possible for 141 patients.
Among the 206 patients, 4 TIA mimics and 1 with perma-
nent atrial fibrillation (unavailable ECG waves for HRV anal-
ysis) were ultimately excluded. Finally, a total of 201 patients
(age=59±10 years; 163 male) were included. Forty-nine patients
were preliminarily diagnosed with TIA, among them 9 were re-
vised to minor stroke based on further imaging tests. Therefore,
ultimately 40 patients (19.9%) were diagnosed as TIA and 161
patients (80.1%) were diagnosed as minor stroke.
Of these 201 patients, 36 cases (17.9%) were identified as
having experienced ischemic events (24 as definite, 8 as prob-
able, 4 as possible). The main ischemic events were ischemic
stroke (n=26; 72%) followed by TIA (n=7; 19%), cardio-
vascular problems (n=2; 6%), and vascular death (1%–3%).
Regarding timing, 17 (47.2%) cases occurred in the first 48
hours after Holter assessment, 28 (77.8%) within 7 days, 30
(83.3%) in 14 days, 32 (88.9%) in 30 days, and 36 (100%) in
90 days. No patient withdrew from the study. Three patients in
the event-free group (out of 165) had unavailable night ECG.
Demographic and clinical information for the study patients
are shown in Table 1.
HRV Predictors and Secondary Ischemic Events
Patients with secondary ischemic events had significantly
lower HRV values (morning HF, 38.1 versus 51.7; P=0.03)
and decreased changes in HRV parameters during daytime
(daytime HF changes, −4.6% versus 18.2%; P<0.001), com-
pared with patients without outcome events. Comparisons of
all HRV parameters, ABCD2 and PSS between 2 groups are
shown in Table 2.
ABCD2 score was analyzed as both continuous and cate-
gorical variables based on published categorization21 (Table 3).
AUCs with 95% CI for all HRV parameters were tested. The
best predictor was daytime HF changes, which showed the
highest AUC of 0.70 in predicting ischemic events, and of
0.72 in predicting ischemic stroke; both were significantly
higher than the AUCs of ABCD2 score used as 2-level cate-
gorical variable (0.57 and 0.58), P<0.01 (Table 3). Analyses
for all HRV data are shown in Table II in the online-only Data
Supplement. Classification performance of HRV is shown in
Table III in the online-only Data Supplement.
HRV-Based Stress Models for
Ischemic Events Prediction
Complete predictive models with HRV parameters, PSS
and ABCD2 scores are shown in Table 3; online-only Data
Supplement. The best stress model (BSM) that included
ABCD2, PSS, and daytime HF changes produced the highest
AUC. We also considered the most practical model (MPM),
in which the ABCD2, PSS, and Morning HF were included.
For ischemic event prediction, BSM had an AUC of 0.82
(Figure 2A). The odds ratio of daytime HF changes (every
10% increases) was 0.84 (95% CI, 0.75–0.92; P<0.001).
MPM gave an AUC of 0.76 (Figure 2A). The odds ratio of
Morning HF (every e-fold increases) was 0.64 (95% CI, 0.43–
0.94; P=0.02). For ischemic stroke prediction, the BSM had
an AUC of 0.87 (Figure 2B), and the MPM had an AUC of
0.82 (Figure 2B). The AUC of both models were significantly
 2010  Stroke  August 2019

Table 1.  Demographic and Clinical Information in the Event Group and Event-Free Group

Patients, N=201
Total Non-Event, Event OR
Clinical and Personal Factors No. (%) Events, N=36 N=165 Rate (%) (95% CI) P Value
Age, y
 ≥60 100 (50.2) 20 80 20.0 1.3 (0.6–2.8) 0.44
 <60 101 (49.8) 16 85 15.8
Sex
 Male 163 (81.1) 30 133 18.4 1.2 (0.5–3.4) 0.71
 Female 38 (18.9) 6 32 15.8
Diagnosis
 TIA 40 (19.9) 9 31 22.5 1.4 (0.6–3.3) 0.40
 Minor stroke 161 (80.1) 27 134 16.8
Atrial fibrillation
 Yes 17 (8.5) 3 14 17.6 1.0 (0.2–3.2) 0.98
 No 184 (91.5) 33 151 17.9
Hypertension
 Yes 113 (56.2) 28 85 24.8 3.3 (1.5–8.1) 0.006
 No 88 (43.8) 8 80 9.1
Diabetes mellitus
 Yes 41 (20.4) 13 28 31.7 2.8 (1.2–6.0) 0.012
 No 160 (79.6) 23 137 14.4
Dyslipidemia
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 Yes 51 (25.4) 14 37 27.5 2.2 (1.0–4.7) 0.043

 No 150 (74.6) 22 128 14.7
Cardiovascular disease
 Yes 46 (22.9) 8 38 17.4 0.9 (0.4–2.2) 0.92
 No 155 (77.1) 28 127 18.1
Cerebrovascular disease
 Yes 49 (24.4) 10 39 20.4 1.2 (0.5–2.7) 0.60
 No 152 (75.6) 26 126 17.1
Smoking
 High dose, y 99 (49.3) 19 80 19.2 1.1 (0.5–2.7) 0.75
 Low dose, y 38 (18.9) 6 32 15.8 0.9 (0.3–2.6) 0.86
 Never 64 (31.8) 11 53 17.2
Drinking
 High dose, y 78 (38.8) 14 64 17.9 1.3 (0.5–3.1) 0.58
 Low dose, y 48 (23.9) 11 37 22.9 1.7 (0.7–4.4) 0.25
 Never 75 (37.3) 11 64 14.7
Medication
 Drugs alone 173 (86.1) 30 143 17.3 1.3 (0.5–3.3) 0.60
 Drugs and operation 28 (13.9) 6 22 21.4
TOAST classification NA NA
 Large-artery atherosclerosis 157 (78.0) 29 128 18.5
 Cardioembolism 14 (7.0) 3 11 21.4
(Continued )

Table 1.  Continued
Total
Clinical and Personal Factors No. (%)
 Lacunar 10 (5.0)
 Other causes 5 (2.5)
 Undetermined causes 15 (7.5)
Recruitment time
 <12 h 85 (42.4)
 12–24 h 63 (31.3)
 24–48 h 53 (26.4)
Cardiovascular diseases include coronary artery disease, myocardial infarction, and unstable angina. A history of cerebrovascular diseases
includes ischemic stroke and TIA. Atrial fibrillation (total 17) includes persistent (5), paroxysmal (5), and unspecified (7) subtypes. Four out of 17
cases of atrial fibrillation were newly detected from 24-h-Holter or Emergency ECG. Operation includes intravenous thrombolysis or endovascular
treatment. NA indicates not applicable; OR, odds ratio; TIA, transient ischemic attack; and TOAST, Trial of ORG 10172 in Acute Stroke Treatment.
higher than the ABCD2 score for both primary and secondary
end point prediction (P<0.02).
For ischemic event prediction, BSM provided a sensitivity
of 90% and a specificity of 61% at a cutoff of event probability
of 13%. MPM provided a sensitivity of 90% and a specificity
of 39% at a cutoff of event probability of 10%. For ischemic
stroke prediction, BSM rendered 90% sensitivity and 72%
specificity at a cutoff of event probability of 12%; and MPM
rendered 90% sensitivity and 61% specificity at the cutoff of
event probability of 9%.
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ESMs for Ischemic Event Prediction
We developed 2 ESMs that combined absolute HRV values,
HRV changes, ABCD2, and PSS. ESM-1 included morning
HF, daytime HF changes, PSS and ABCD2 score. In ESM-2,
we used cutoffs of daytime HF changes (12%) and morning
HF (50 ms2) based on the maximum Youden’s index to de-
fine the 3 risk levels. For ischemic event prediction, the AUC
of ESM-1 was 0.84 and AUC of ESM-2 was 0.82 (Table 3);
both were significantly higher than ABCD2 score (P<0.001)
(Figure 3A). Similarly, for ischemic stroke prediction, both
ESM-1 (AUC=0.89) and ESM-2 (AUC=0.86; Table 3) sig-
nificantly improved the AUC compared with ABCD2 score
(P<0.001; Figure 3B). Classification performance of explora-
tory HRV models is shown in the online-only Data Supplement.
Discussion
In this study, we show that HRV parameters, used as a proxy
for ANS function and stress in patients with TIA or minor
stroke, can yield superior predictive values for the occurrence
of secondary ischemic events than the ABCD2 score.
Our results show that morning HF may predict the occur-
rence of ischemic events (AUC=0.61 for ischemic events and
0.62 for ischemic stroke). The lower values of morning HF
in event-group patients indicate lower PNS activity and im-
paired PNS contributions to stress response.6,10 This is a sign
of high overall stress from both chronic and acute sources.6,10
Although no study, to our knowledge, has focused on a popu-
lation of TIA/minor stroke to examine the association between
decreased HF and increased risk of recurrent ischemic events,
Guan et al   ANS and Stress in TIA and Minor Stroke   2011
Patients, N=201
Non-Event, Event OR
Events, N=36 N=165 Rate (%) (95% CI) P Value
2 8 20.0
1 4 20.0
1 14 6.7
18 67 21.2 2.1 (0.8–6.2) 0.14
12 51 19.0 1.8 (0.7–5.7) 0.26
6 47 11.3
our results are supported by previous findings in the stroke
literature showing that patients with ischemic stroke have
decreased HF compared with healthy controls22; furthermore,
lower HF was correlated with a higher risk of stroke.23
We found that daytime HF changes were significantly dif-
ferent between event (−4.6%) and event-free groups (18.2%),
P<0.001, which indicates PNS improvement in patients
without outcome events, and dysfunctional PNS response in
those with events. Daytime HF changes provide the highest
AUC of 0.70 for our primary end point and 0.72 for secondary
end point among all HRV parameters(Table 3). The changes
in HF, as a measure of dynamic PNS function/activity in re-
sponse to stress after initial TIA or minor stroke, may repre-
sent an indicator of the body’s ability to handle stress and thus
an indicator of the individual’s recovery capacity (rebound
effect). The uncoupling and recoupling theory proposed by
Ellenby et al24 supports this statement. The uncoupling theory
posits that during an uncontrolled stressful situation, the organ
responsiveness to autonomic signaling is diminished with
decreased HRV, and this trend progresses with the severity
of the condition.25 Conversely, the recoupling process shows
HRV recuperation (ie, return of parasympathetic activity) as a
sign of recovery from stress, restoration of homeostasis, and
thus an improved health condition.24
Our study is the first to document the possible use of dy-
namic changes of in ANS parameters to predict the occurrence
of ischemic events after TIA or minor stroke. These results are
supported by other studies examining cardiovascular diseases,
which that showed that HRV indices were more depressed
in the early phase after acute myocardial infarction and sub-
stantially improved during the recovery phase.26 On the other
hand, decreased HF after initial ischemic stroke was corre-
lated with poor prognosis.27
In our study, we developed several HRV-based stress
predictive models. For both ischemic events and ischemic
stroke prediction, these models provided significantly higher
AUCs (between 0.75 and 0.87) compared with ABCD2 score
(P<0.05; Table 3). The BSM generates the best AUC of 0.82
and 0.87 among all models (Figure 2) with comparable pre-
dictive performance to imaging testing.3 After validation,
 2012  Stroke  August 2019

Table 2.  Comparisons of HRV Parameters, PSS and ABCD2 Between the Event Table 2.  Continued
Group and Event-Free Group
Patients With
Patients With Patients With Event-Free P
Patients With Event-Free P Events (N=36) (N=165)* Value†
Events (N=36) (N=165)* Value†
  Day-night HF 0.140 0.108 0.28
HRV values, median (IQR) norm changes (0.020–0.265) (0.009–0.207)
 HF, (ms2)   Morning-night HF 0.139 0.128 0.70
  Morning HF 38.1 51.7 0.03 norm changes (0.036–0.231) (0.033–0.246)
(21.6–65.8) (27.9–112.1)  HF+LF changes (%)
  Day HF 38.8 59.9 0.001   Daytime HF+LF −22.1% 2.9% 0.002
(21.8–50.5) (29.6–120.9) changes (−35.3% to 1.1%) (−19.9% to 36.0%)
  Night HF 116.4 138.1 0.15   Day-night HF+LF 87.7% 40.9% 0.03
(55.2–146.1) (62.4–267.8) (22.7% to 170.1%) (1.4% to 113.3%)
  24-h HF 80.7 100.9 0.06   Morning-night 79.8% 49.9% 0.28
(46.6–101.6) (50.2–187.9) HF+LF changes (9.5% to 178.0%) (7.2% to 126.9%)
 HF norm (n.u.)  TP changes (%)
  Morning HF norm 0.21 0.28 0.10   Daytime TP −9.8% 1.8% 0.03
(0.17–0.35) (0.19–0.39) changes (−27.7% to 13.0%) (−21.2% to 33.2%)
  Day HF norm 0.23 0.29 0.01   Day-night TP 90.9% 67.6% 0.64
(0.16–0.35) (0.22–0.42) changes (22.0% to 131.1%) (14.4% to 137.2%)
  Night HF norm 0.38 0.44 0.32   Morning-night TP 91.3% 70.4% 0.99
(0.22–0.56) (0.30–0.58) changes (17.4% to 127.7%) (19.1% to 133.4%)
  24-h HF norm 0.32 0.37 0.06 PSS score, mean (SD) 20.2 (3.0) 17.8 (3.4) <0.001
(0.24–0.40) (0.27–0.49)
ABCD2 score, mean 5.1 (1.4) 4.4 (1.5) <0.001
 HF+LF (ms2) (SD)
  Morning HF+LF 165.7 210.0 0.16 TP is the sum of HF, LF, and VLF. ABCD2 indicates age, blood pressure,
(100.7–291.5) (111.9–326.8) clinical features, duration of symptoms, diabetes; HF, high frequency; HF norm,
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  Day HF+LF 152.0 220.0 0.04 normalized HF; HRV, heart rate variability; IQR, interquartile range; LF, low
(96.1–232.5) (114.3–329.0) frequency; n.u., normalized unit; PSS, Perceived Stress Scale; TP, total power;
and VLF, very low frequency.
  Night HF+LF 261.4 300.4 0.32 *Sample size for the analyses involving nighttime is 162.
(209.2–412.0) (181.2–586.5) †In Wilcoxon-rank-sum test.
  24-h HF+LF 204.0 264.0 0.09
(169.7–347.2) (163.6–467.8) BSM could be used to calculate the probability of outcome
 TP, (ms2) events for each individual. Another crucial advance com-
  Morning TP 457.0 577.0 0.30
pared with imaging is that BSM can be used in any clinical
(368.1–755.1) (367.7–821.0) or home setting. However, testing dynamic changes of HRV
requires an entire day of Holter monitoring, which delays de-
  Day TP 424.2 574.8 0.17
(327.6–755.2) (349.8–838.0)
cision-making. The MPM could then be used as it also signifi-
cantly improves the predictive power of ABCD2 score to 0.76
  Night TP 900.6 958.9 0.13
and 0.82 (P=0.02; Figure 2). The MPM has several positive
(529.8–1120.0) (637.0–1505.0)
features: (1) it only necessitates assessment of HRV during
  24-h TP 718.8 772.7 0.10 a short time period, thus enabling rapid decision-making; (2)
(481.9–913.8) (557.3–1189.0)
it provides an earlier response, therefore, may capture more
HRV changes, median (IQR) outcomes; and (3) it represents the patient’s baseline stress
 HF changes (%) profile. For these reasons, the MPM is well suited to an emer-
  Daytime HF −4.6% 18.2% <0.001 gency environment, where time is limited and physicians need
changes (−28.9% to 12.8%) (−6.1% to 62.2%) to conduct rapid assessment of patients.
In the 2 ESMs, ESM-1 provides excellent predictive
  Day-night HF 177.4% 90.8% 0.01
changes (55.5% to 423.9%) (35.4% to 197.2%) power whereas ESM-2 is simpler to use. Improvement in their
predictive power illustrate the importance of considering both
  Morning-night HF 154.6% 128.1% 0.35
HF baseline values and its changes during the day, as they
changes (42.9% to 423.5%) (43.6% to 277.6%)
collectively measure the baseline stress and body rebound ca-
 HF norm changes (n.u.) pacity after initial stress.
  Daytime HF norm 0.021 0.050 0.02 Our results invite more research into the area of using both
changes (−0.043–0.073) (−0.019–0.125) the baseline values of HRV parameters and their changes over
(Continued ) time to predict an individual’s health status and recovery capacity
 Guan et al   ANS and Stress in TIA and Minor Stroke   2013

Table 3.  Predictive Values of Selected HRV-Based Stress Models for the Occurrence of Ischemic Events and Ischemic Stroke in the Subsequent 90 Days

Ischemic Events Stroke

Models OR (95% CI) P Value AUC (95% CI) OR (95% CI) P Value AUC (95% CI)
Univariate models
 Model with ABCD2 alone
  ABCD2 as continuous variable 1.39 (1.07–1.84) 0.01 0.63 (0.53–0.73) 1.46 (1.08–2.03) 0.02 0.64 (0.53–0.75)
  ABCD2 as 2-level categorical variable 0.57 (0.50–0.63) 0.58 (0.51–0.65)
  <4 1
  ≥4 2.33 (0.92–7.14) 0.10 2.82 (0.92–12.25) 0.10
  ABCD2 as 3-level categorical variable 0.61 (0.52–0.71) 0.62 (0.52–0.72)
  0–3 1
  4–5 1.80 (0.66–5.80) 0.28 2.24 (0.67–10.18) 0.23
  6–7 3.37 (1.19–11.14) 0.03 3.92 (1.13–18.16) 0.046
  Model with PSS alone 1.23 (1.10–1.38) <0.001 0.72 (0.63–0.8) 1.32 (1.16–1.52) <0.001 0.77 (0.68–0.86)
 Model with HRV alone
  Morning HF 0.68 (0.47–0.96) 0.03 0.61 (0.52–0.71) 0.67 (0.45–1.00) 0.049 0.62 (0.51–0.73)
  Daytime HF changes 0.83 (0.75–0.91) <0.001 0.70 (0.62–0.79) 0.80 (0.70–0.89) <0.001 0.72 (0.63–0.82)
Bivariate models
 Morning HF+ABCD2 0.64 (0.43–0.92) 0.02 0.68 (0.58–0.77) 0.63 (0.41–0.96) 0.03 0.70 (0.60–0.80)
 Daytime HF change+ABCD2 0.84 (0.75–0.92) <0.001 0.74 (0.67–0.82) 0.81 (0.71–0.91) <0.001 0.77 (0.68–0.85)
 PSS+ABCD2 1.21 (1.09–1.36) <0.001 0.74 (0.66–0.83) 1.29 (1.14–1.50) <0.001 0.80 (0.71–0.88)
 Morning HF+PSS 0.65 (0.45–0.94) 0.02 0.73 (0.64–0.82) 0.63 (0.41–0.97) 0.04 0.79 (0.70–0.88)
 Daytime HF changes+PSS 0.84 (0.75–0.92) <0.001 0.80 (0.72–0.87) 0.80 (0.70–0.90) <0.001 0.85 (0.79–0.92)
Downloaded from http://ahajournals.org by on April 2, 2020

Full models
 Morning HF+PSS+ABCD2 (MPM) 0.64 (0.43–0.94) 0.02 0.76 (0.67–0.84) 0.63 (0.40–0.97) 0.04 0.82 (0.73–0.90)
 Daytime HF change+PSS+ABCD (BSM) 0.84 (0.75–0.92) <0.001 0.82 (0.75–0.88) 0.81 (0.71–0.91) <0.001 0.87 (0.81–0.93)
Exploratory models
 ESM-1: morning HF+daytime HF Morning HF: 0.55 0.006 0.84 (0.78–0.90) Morning HF: 0.53 0.01 0.89 (0.84–0.95)
changes+PSS+ABCD2 (0.35–0.83) (0.32–0.85)
Daytime HF changes: <0.001 Daytime HF changes: <0.001
0.83 (0.73–0.91) 0.79 (0.68–0.89)
 ESM-2: risk level+PSS+ABCD2 0.82 (0.75–0.89) 0.86 (0.79–0.93)
 Medium risk (compared with low risk) 17.52 (3.17–332.82) 0.008 11.27 (1.85–223.32) 0.002
 High risk (compared with low risk) 39.58 (6.78–769.10) <0.001 33.40 (5.36–691.16) <0.001
Analyses of all HRV data are provided in Table II in the online-only Data Supplement. ABCD2 score indicates age, blood pressure, clinical features, duration of
symptoms, diabetes; AUC, area under the curve; ESM-1, exploratory stress model-1; ESM-2, exploratory stress model-2; HF, high frequency; HRV, heart rate variability;
and PSS, Perceived Stress Scale.

and, therefore, the risk of future ischemic events. If these results
are verified, they provide relevant information for the medical
management of patients with TIA or minor stroke. Using HRV,
especially the HF-related variables that represent PNS activity,
would help identify more accurately the group at highest risk
of developing an ischemic event that needs more attention. This
stress profile may provide a cue that is different from the in-
formation that imaging or/and other traditional tools provides;
thus, this assessment may identify a specific population that is
at higher risk and requires additional vigilance and medical care.
If our results are validated, it is tempting to speculate that
specific interventions targeted toward ANS modulation, in
addition to traditional treatment, may reduce the risk or delay
the occurrence of ischemic events. We have considered the
hypothesis that ANS dysfunction could be a potential cause
or herald of future stroke. A recent study shows the roles of
ANS imbalance and atrial cardiopathy as possible pathogenic
factors underlying cryptogenic strokes; ECG markers have
then been proposed to detect an altered atrial substrate, which
might be predictive of cryptogenic stroke, at an early stage.28
This theory deserves future specific study validation.
Our data provide compelling evidence of the ability to
enhance risk stratification for future ischemic events in at-
risk patients using HRV analyses. However, there are some
 2014  Stroke  August 2019

Figure 2.  ROC curves of ABCD2 score (age, blood pressure, clinical features, duration of symptoms, diabetes), most practical model (MPM), and best stress
model (BSM) to predict ischemic events and ischemic stroke in the subsequent 90 d. A, ROC curves of ABCD2 score, BSM, MPM in predicting ischemic
events in 90 d. B, ROC curves of ABCD2 score, BSM, MPM in predicting ischemic stroke in 90 d. AUC indicates area under the curve; and ROC, receiver op-
erating characteristic.

limitations to our study approach. While we took care to
maintain objectivity in assessing exposure and outcomes, it
is possible that some biases remain. Outcome events were
assessed blinded from knowledge of the participants’ HRV
data. Further, the researcher who conducted HRV analysis and
the neurologists who evaluated outcome events were blinded
to outcome and exposure status, respectively. Although con-
Downloaded from http://ahajournals.org by on April 2, 2020
be inferred to other TOAST categories. We recommend then
conducting larger studies in the future with enough power to
assess the predictive value of HRV parameters in different cat-
egories of stroke diagnosis. Finally, we did not have precise
information regarding all medications used by the patients in
this study. Although some drugs, like β-blockers, influence
the ANS, and hence HRV, we decided not to exclude patients

ducted in a very active hospital, we were only able to recruit
201 patients because of the time constraint to recruit patients
within 48 hours of the initial ischemic event; this limited
sample size prevented the conduct of sub-group analyses (for
instance, by TOAST categories). Our subgroup analysis on
large-artery atherosclerosis patients (78% of study patients;
Table 1) did not show any major difference with the whole
population analysis; however, at this stage, the results cannot
using drugs with the potential to influence ANS function; the
reason to prescribe these drugs is related to stress and using
these drugs represents another stressor for the body. The asso-
ciation we found between HRV parameters and the risk of fu-
ture ischemic events was detected despite the extra noise (but
not systematic bias) created by using concomitant drugs by
patients and better reflects the clinical reality of these patients.
Finally, we selected the predictors that we believed important

Figure 3.  ROC curves of ABCD2 score (age, blood pressure, clinical features, duration of symptoms, for diabetes), exploratory stress model-1 (ESM-1), and
exploratory stress model-2 (ESM-2) to predict ischemic events and ischemic stroke in the subsequent 90 d. A, ROC curves of ABCD2 score, ESM-1, and
ESM-2 in predicting ischemic events in 90 d. B, ROC curves of ABCD2 score, ESM-1, and ESM-2 in predicting ischemic stroke in 90 d. AUC indicates area
under the curve; and ROC, receiver operating characteristic.
 Guan et al   ANS and Stress in TIA and Minor Stroke   2015
to generate a comprehensive stress profile for ischemic events
prediction. These models need to be validated in other studies.
Conclusions
Overall, our study shows that assessing stress expression
through HRV and its changes over a discrete time period
after TIA or minor stroke may have clinical utility in iden-
tifying patients at a high risk of developing secondary is-
chemic events. By assessing ANS dysfunction and individual
stress profiles, specific at-risk individuals or populations may
be identified for targeted management. These results, while
promising, need to be verified in other studies before changes
of practice are recommended.
Acknowledgments
We appreciate all physicians, especially Dr Xingquan Zhao, Dr Weiqi
Chen, and Dr Xin Liu, in Department of Neurology at Beijing Tiantan
Hospital provided supports on study recruitment. Dr Hui Lin and
Dr Zheng Liu and all specialists in the Cardiac Electrophysiology
Laboratory helped with scheduling the Holter testing.
Sources of Funding
Dr Collet is supported in part by a scholarship of the BC Children’s
Hospital Research Institute in Vancouver, Canada.
Disclosures
None.
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Downloaded from http://ahajournals.org by on April 2, 2020
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