Pediatric Cardiology

https://doi.org/10.1007/s00246-019-02216-x

ORIGINAL ARTICLE

Orthostatic and Exercise Effects in Children Years After Kawasaki

Disease
Yoshihiro Nakamura1,5   · Takehiro Hama2,6 · Yoshie Nakamura3 · Hideki Tsukada1 · Yoichiro Oda2 · Shoichi Awa4

Received: 7 August 2019 / Accepted: 25 September 2019

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Abstract
The long-term orthostatic and/or exercise hemodynamic effects in children years after Kawasaki disease (KD) were studied
using clinical data from the treadmill exercise test (TMET). Heart rate (HR) and blood pressures (BPs) recorded in TMET
were compared between two age, gender, and body scale-matched groups of patients with and without a history of KD.
The KD group included 60 patients (9.8 ± 2.7 years old) 6.6 ± 2.6 years after KD without coronary arterial aneurysm. The
non-KD group included 60 children (10.2 ± 2.7 years old) with other diagnoses. The exercise tolerance in TMET was not
statistically different between the two groups. The KD group had a faster HR on standing than the non-KD group by 8.6%
(101.5 ± 12.2 vs. 93.5 ± 15.9 bpm, respectively; P < 0.01), suggesting weaker and/or retarded orthostatic vasoconstriction.
The pulse pressure was largely augmented above the 4th stage beyond 160 mmHg in 10.6 versus 0% (5 vs. 0) of the KD and
non-KD groups (P < 0.05), respectively, while HR and BPs were not significantly different through exercise stages between
the two groups. The KD group also showed a faster HR recovery five minutes after exercise than the non-KD group, by 5.7%
(108.0 ± 11.6 vs. 102.2 ± 14.2 bpm, respectively; P < 0.05). Our results might indicate long-term subclinical impacts on the
vascular tonus of children years after the disease that have not been recognized in previous studies.

Keywords  Kawasaki disease · Treadmill exercise test · Heart rate · Blood pressure · Systemic vascular resistance

Introduction

Kawasaki disease (KD) is well known as a self-limited dif-

fuse vasculitis syndrome in infants and young children,
where medium-sized arteries like coronary arteries are
specifically affected [1–3]. Although KD has an aspect of
Shoichi Awa was retired from the Kyorin University School of
Medicine.

2
* Yoshihiro Nakamura Department of Pediatrics, Chigasaki Municipal Hospital,
yonakamura‑tky@umin.ac.jp 5‑15‑1, Motomura, Chigasaki City, Kanagawa 253‑0042,
Japan
Takehiro Hama
3
m1109004@yahoo.co.jp Department of Pediatrics, Toto Bunkyo Hospital (former
Kodaira Memorial Tokyo Hitachi Hospital), 3‑5‑7, Yushima,
Yoshie Nakamura
Bunkyo‑ku, Tokyo 113‑0034, Japan
y.nakamura.toubyo@siren.ocn.ne.jp
4
Department of Pediatrics, Kyorin University School
Hideki Tsukada
of Medicine, 6‑20‑2, Shinkawa, Mitaka City,
tsukahide@hb.tp1.jp
Tokyo 181‑8611, Japan
Yoichiro Oda 5
Department of Pediatrics, Graduate School of Medicine,
yo‑oda@umin.ac.jp
University of Tokyo, 7‑3‑1 Hongo, Bunkyo‑ku,
Shoichi Awa Tokyo 113‑8655, Japan
sho‑mi.awa@chic.ocn.ne.jp 6
Nozomi Pediatric Clinic, 4‑373, Youkaichi, Kanazawa City,
1 Ishikawa 921‑8064, Japan
Department of Pediatrics, Yatsu Hoken Hospital, 4‑6‑16,
Yatsu, Narashino City, Chiba 275‑0026, Japan

13
Vol.:(0123456789)

over-activated immune disease, the causes and precise mech-
anism of KD have yet to be sufficiently elucidated [1–3].
While such morphologic changes as aneurysm and/or
dilatation of coronary arteries are well-known [1, 2], the
depressed endothelial functions [4] and altered wall-prop-
erties [5–8] of systemic arteries also chronically remain
in patients with coronary arterial aneurysm (CAA) and
regressed CAA, and even in those without coronary arterial
complications long after its acute stage [6, 9–12]. Experts
have been concerned about these possible impaired arterial
functions and wall properties increasing the risk of athero-
sclerotic cardiovascular disease in adulthood [13, 14]. Fur-
thermore, persistent increments of both circulating endothe-
lial cells [15] and high-sensitivity C-reactive protein [16]
were reported in around 10-year-old patients late after KD
even without CAA, suggesting persistent endothelial cell
damage and low-grade inflammation, respectively. However,
the long-term effects of these chronic findings on patients’
exercise physiologies after KD are unclear because the exer-
cise data have not been sufficiently studied.
The treadmill exercise test (TMET) has been recognized
as a non-invasive and highly sensitive method for detect-
ing coronary arterial diseases and evaluating the dynamic
cardiac function, and it has been dominantly used with the
Bruce protocol [17, 18]. TMET has also been applied in
pediatric research [19, 20], including a recent study incorpo-
rating the Bruce protocol into ramp tests [21, 22]. In addition
to electrocardiography (ECG), the heart rate (HR, bpm), and
systolic (SP, mmHg) and diastolic (DP, mmHg) blood pres-
sures are routinely monitored in TMET.
In this study, with records of TMET in children with and
without a history of KD, we compared the means of HR
and BPs as responses to standing and exercise between the
two groups to determine the long-term orthostatic and/or
exercise effects in children years after KD.
Table 1  The two age, sex, body n Age (y.o.)
scale, and hospital-matched
groups with Kawasaki disease KD 60 9.8 (2.7)
(KD) and without it (Non-KD)
Non-KD 60 10.2 (2.7)
in this study
P-value 0.526
n number of patients, y.o. years old, M male, F female, BW body weight, BH body height, BSA body sur-
face area, P probability. Hosp. indicates the number of treadmill exercise tests performed in three medical
institutions, Y, C, and K represent Yatsu Hoken, Chigasaki Municipal, Kodaira Memorial Tokyo Hitachi
Hospitals, respectively. Parametric data are presented as the mean with one standard deviation (parenthe-
ses)
13
Pediatric Cardiology
Methods
Subjects
Data were collected from the database of child TMETs
performed in the three medical facilities of Yatsu Hoken,
Chigasaki Municipal, and Kodaira Memorial Tokyo Hitachi
Hospitals from September 1998 to September 2017. A total
of 127 records of TMET were accessible, including 64
asymptomatic patients with a past history of KD and 63
patients without it. Since some children underwent TMET
twice, second records of 3 males and 1 female after KD and
those of 2 males and 1 female without KD were excluded
from the analysis. As a result, this study finally enrolled 60
patients in a KD group and 60 in a non-KD group. There
was no significant difference between the two groups with
regard to age, sex, body weight (BW), or body height (BH),
as presented in Table 1. Subjects were distributed among
the three hospitals without a significant difference (Table 1).
Child patients in the KD group had a mean KD onset age
of 3.1 ± 2.4 years old (y.o.) (n = 54) and underwent TMET
6.6 ± 2.6 years (n = 54) after the onset, while the KD onset
age was unknown in 6 patients. Diagnosis, acute therapy,
and chronic follow-up had been performed based on standard
criteria and guidelines [1, 2]. Although all of these patients
passed their private and school times after remission of KD
as normally as other healthy normal students did, TMETs
had been performed in them to examine ischemic findings
of ECG and exercise tolerance before they advanced the
level of exercise in school and/or in private activities. One
13-year-old female patient experienced relapses of KD twice
before TMET. Dilated coronary arteries had been detected
in a 10-year-old female transiently in the acute period at
1 year of age, with a 3-mm diameter of the left main coro-
nary artery (LMCA), and in a 12-year-old male with a 4.5-
mm diameter LMCA that had been present since 4 years of
age, both of whom had not been treated with anticoagulants
after the catheter coronary angiography.
Sex (M/F) BW (kg) BH (cm) Hosp. Y/C/K
29/31 35.2 (11.9) 138.5 (16.7) 35/23/2
30/30 35.7 (11.4) 140.9 (16.2) 34/26/0
0.897 0.814 0.431 0.577
Pediatric Cardiology

All children in the non-KD group were also as healthy as
normal children, with no medications or restrictions of exer-
cise in their private and school lives. We could thus consider
the non-KD group as a substitute for a normal physiologi-
cal control. Diagnoses and symptoms in the non-KD group
were: 2 cases of atrioventricular block (one first degree and
one second degree by Wenckebach classification), 3 cases
of suspected cardiomyopathy (2 isolated non-compaction
cardiomyopathies and the other of an unspecified type) with
a normal cardiac function, 2 cases of remitted rheumatic-
myocarditis, 13 cases of chest pain, 1 case of long QT syn-
drome, 1 case of supraventricular and 25 cases of ventricular
paroxysmal contractions, and 13 cases of Wolf-Parkinson-
White syndrome.
No medications or diseases that could influence cardio-
vascular functions were identified on TMET in patients of
these two groups.
TMET
All TMETs were performed based on the standard Bruce
protocol [17, 18]. Patients underwent the TMET after the
physician had accepted their and/or their parents’ informed
consent. HR was determined through ECG, and both systolic
and diastolic blood pressure (SP and DP, respectively) auto-
matically measured at the brachial artery by sphygmoma-
nometry with the cuff method were recorded by computer
in supine (spn) and then standing (std) positions, in the 1st
through 6th exercise stages, and in recovery (rcv).
Stabilized parameters in the supine and standing positions
were measured 3 min after lying or standing, respectively,
although supine data had been recorded only in Yatsu-Hoken
Hospital. HR and BPs were measured during exercise when
2 min had elapsed since the initiation of each exercise stage,
which lasts 3 min in the Bruce protocol [17, 18]. Recovery
data were measured in a sitting position on a bed 5 min after
terminating the exercise test.
Hereafter, numerals and abbreviations suffixed to param-
eters represent the sequential number of exercise stages in
the Bruce protocol and the situation of patients in TMET,
respectively.
Data Analysis
Initially, exercise tolerance was compared between KD and
non-KD groups based on the final exercise stage of TMET
that could be reached. The HR, SP, DP, and pulse pres-
sure (PP), which was the result from SP minus DP, were
compared between KD and non-KD groups in each stage
of TMET.
Data are presented as the mean ± one standard devia-
tion (SD). Welch’s t-test was used for comparison of the
mean value between the two groups after Fischer’s F-test
for homoscedasticity. The standard χ2 test was also applied
for evaluating the significance of nonparametric outcomes
between the two groups. P-values are presented by the two-
sided test and P < 0.05 was considered significant.
Ethical Procedure
Using the clinical data of patients for this study was per-
mitted by the ethical commission of each hospital as this
retrospective study and each TMET obeyed to the 1975 Dec-
laration of Helsinki guidelines.

Table 2  Comparisons of the number of patients in each stage and the final one of TMET between KD and non-KD groups
A. The number of patients at each stage of TMET whose data were included in this analysis
Stages of TMET
Spn Std 1st 2nd 3rd 4th 5th 6th Rcv

KD 35 60 60 60 56 47 22 3 59
Non-KD 33 59 59 60 57 45 12 3 59
B. The number of patients in the final stage of TMET in the two groups
Final stage of TMET
2nd 3rd 4th 5th 6th

KD 2 5 29 21 3
Non-KD 2 7 33 13 5

P = 0.994 and 0.960 in A and B, respectively

TMET treadmill exercise test, KD Kawasaki disease, spn supine, std standing, rcv recovery, P probability

13
 Pediatric Cardiology

Results Parameters

The number of patients whose data could be included in our
estimation of the hemodynamics is presented at each stage of
TMET in Table 2A, with no significant differences between
KD and non-KD groups.
Exercise Tolerance
The number of patients in the final exercise stage of TMET
is indicated in the two groups in Table 2B, with no signifi-
cant difference between them in the distribution of patients
in each final stage. The average of the final exercise stage
reached by patients was 4.3 ± 0.8 versus 4.2 ± 0.6 for KD
and non-KD (P = 0.466), respectively. Neither chest pain nor
abnormal ST-T change was noted in any TMETs.
HR, SP, DP, and PP are presented in Fig. 1a–d, respectively.
Supine and Standing
The KD group had a significantly faster H ­ R std than the
non-KD group (101.5 ± 12.2 vs. 93.5 ± 15.9 bpm, respec-
tively; P = 0.003) (Fig. 1a), while the means of SP, DP, and
PP were not significantly different between the two groups
(Fig. 1b–d, respectively).
Exercising
HR, SP, DP, and PP were not significantly different
between the two groups (Fig. 1a–d, respectively).

KD
a 250 b 250 Non-KD
*
200 200
SP [mmHg]

150 150
HR [bpm]

100 100

50 50

0 0
spn std 1st 2nd 3rd 4th 5th 6th rcv spn std 1st 2nd 3rd 4th 5th 6th rcv

c 120 d 160

120
80
DP [mmHg]

PP [mmHg]

80

40
40

0 0
spn std 1st 2nd 3rd 4th 5th 6th rcv spn std 1st 2nd 3rd 4th 5th 6th rcv

Fig. 1  Heart rate and blood pressures of Kawasaki disease (KD) and
non-KD groups in the treadmill exercise test using the Bruce proto-
col. a Heart rate (HR), b Systolic blood pressure (SP), c Diastolic
blood pressure (DP), and d Pulse pressure (PP) at each stage of the
Bruce protocol. Indicators of spn and std, sequential numbers, and rcv
refer to supine and standing positions, exercise stages, and recovery,
respectively. Means are indicated with the standard deviation using
vertical outliers. * and † refer to P < 0.05 and P < 0.001 by Welch’s
t-test, respectively

13
Pediatric Cardiology
KD and non-KD groups contained six of 60 (10.0%)
versus one of 60 (1.7%) cases with an augmented PP
beyond 160 mmHg at stages 1 to 6 (P = 0.051), respec-
tively. However, since one patient out of these cases
terminated TMET at stage 3 in each group, five of 47
(10.6%) and zero of 45 (0%) children showed a markedly
augmented PP greater than 160 mmHg after stage 4 in KD
and non-KD groups, respectively (P = 0.024).
Recovery
HRrcv was significantly faster in KD group than in non-KD
(108.0 ± 11.6 vs. 102.2 ± 14.2 bpm, respectively; P = 0.017)
(Fig. 1a).
Discussion
Despite the relatively small population, this study identified
some significant differences in ­HRstd and H ­ Rrcv between the
two groups, indicating previously unreported clinical fea-
tures years after KD.
The faster ­HRstd in children with remitted KD might be
explained by the deterioration or retardation of systemic
arterial contraction in response to standing, and it could be
accounted for by the stiffened wall properties of systemic
arteries [9, 11, 12]. The brachial-ankle pulse wave velocity
(baPWV) was reported to be significantly faster, at 110%
of normal (P < 0.01), in 90 patients (13 ± 5 y.o.) after KD
irrespective of being with or without CAA [12]. Similarly,
a significantly faster PWV of the brachio-radial arterial seg-
ment, by 13.9%, than controls (P = 0.04) was also reported
in 29 remitted KD patients (8.9 ± 3.2 y.o.) without CAA [5].
The KD group’s slightly faster H ­ Rrcv 5 min after exercise,
by 5.8 bpm (5.7%), could also be related to factors that made
­HRstd faster in the KD group. In addition, it could be caused
by the depressed vagal reactivation in patients in the KD
group because of atherosclerotic [6, 11] and inflammatory
[23] changes of the carotid artery after KD although this is
our speculation. Cheung et al. (2007) reported a significantly
increased carotid intima-media thickness (IMT) and carotid
arterial stiffness index in 24 patients (8.6 ± 3.3 y.o.) after KD
without CAA by ultrasonography [6]. Oguri et al. (2014)
recently reported subclinical and mild sclerotic changes of
the common carotid artery in 75 young patients (8.2 ± 2.8
y.o.) with a history of KD using 2-dimensional ultrasound
speckle tracking [11]. The vagal reactivation was reported
to be related to immediate HR recovery, especially during
the 1st minute after exercise. In healthy middle and old-age
adults, a small reduction of ≤ 12 bpm [24] or ≤ 18 bpm [25]
was a strong predictor of mortality, although the mechanism
has yet to be fully clarified.
We did not find any significant differences in exercise
tolerance or HR and BP responses (Fig.  1a–d). Paridon
et al. [26] reported normal maximum oxygen consumption
( V̇ O2 max) in 46 patients (10 ± 3 y.o.) late after KD regard-
less of their coronary artery status. Gravel et al. (2014)
recently reported no significant differences in HR, SP, and
DP responses to exercise in TMET between 133 patients
late after KD with CAA (11.0 ± 2.7 y.o.) and 117 without it
(10.7 ± 2.7 y.o.), not including non-KD controls [27].
However, there was a significant difference in the
prevalence of individuals with a markedly augmented PP
(>160 mmHg) through the 4­ th to 6­ th stages between KD
and non-KD groups although the subject populations in this
study were insufficient to definitively establish such an effect
after KD. The seven patients whose PP exceeded 160 mmHg
in this study probably should be treated as having exercise-
induced arterial hypertension (EIAH), which would predict
future cardiovascular disorders [28–30], though there are
no definite criteria for EIAH in children. The six patients
in the KD group could have been affected by the depression
of endothelium-dependent and flow-mediated vasodilation
[10], and/or augmentation of arterial wall stiffness reported
in children after KD without CAA in the literature [6, 9,
11, 12].
Limitations
Because the arterial pressure was reported to fluctuate on
exercise, especially when HR and the step rate were not syn-
chronized, the measurement of BPs by sphygmomanometers
would largely depend on the peak or nadir of phasic fluctua-
tion [31]. The mechanisms leading to both faster H­ Rstd and
­HRrcv in the KD group remain unknown through our study.
HR recovery should be examined 1 min after exercise in
TMET in future study. Normal healthy controls would have
been more preferable than our non-KD patients.
Conclusions
Our KD group showed a significantly faster HR in standing
and recovery conditions than non-KD children, and a signifi-
cantly higher number of patients with augmented PP under
the more intense exercise condition, while no significant
difference was found in HR and BP responses to exercise
between the two groups. Although the results of this study
could be explained by atherosclerotic findings reported in
the children after KD, future studies are required to reveal
the precise phenomenon, its mechanisms, and the future
implications for these patients.
13
 Pediatric Cardiology

Acknowledgement  The corresponding author YN is grateful to the Prevention, American Heart Association Council on Nutrition, Phys-
medical, nursing, and paramedical staff in each hospital for partici- ical Activity, and Metabolism, American Heart Association Coun-
pating and supporting the collection of clinical records used in this cil on High Blood Pressure Research, American Heart Association
retrospective study. Council on Cardiovascular Nursing, American Heart Association
Council on the Kidney in Heart Disease, Interdisciplinary Working
Group on Quality of Care, and Outcomes Research (2006) Cardio-
Compliance with Ethical Standards  vascular risk reduction in high-risk pediatric patients: a scientific
statement from the American Heart Association Expert Panel on
Conflict of interest  The authors declare that they have no conflict of Population and Prevention Science; the Councils on Cardiovascu-
interest. lar Disease in the Young, Epidemiology and Prevention, Nutrition,
Physical Activity and Metabolism, High Blood Pressure Research,
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