Left Ventricular Myocardial and Hemodynamic

Response to Exercise in Young Patients after

Endovascular Stenting for Aortic Coarctation
Ching Kit Chen, MD, Barbara Cifra, MD, Gareth J. Morgan, MD, Taisto Sarkola, MD, Cameron Slorach, RDCS,
Hui Wei, MD, Timothy J. Bradley, MBChB, Cedric Manlhiot, BSc, Brian W. McCrindle, MD,
Andrew N. Redington, MD, Lee N. Benson, MD, and Luc Mertens, MD, PhD, Toronto, Ontario, Canada

Background: Endovascular stenting has emerged as a treatment option for children with coarctation of the
aortic (CoA), but the impact on left ventricular (LV) function has been poorly documented. The aim of this
study was to characterize the LV myocardial and hemodynamic response to exercise in young patients
who underwent endovascular stenting for CoA during childhood using semisupine bicycle exercise stress
echocardiography.

Methods: This was a single-center prospective cross-sectional study including 30 patients with CoA and 30
age- and gender-matched control subjects who underwent semisupine bicycle exercise stress echocardiog-
raphy. Color Doppler tissue imaging peak systolic (s0 ) and early diastolic (e0 ) velocities in the LV lateral wall and
basal septum, LV myocardial acceleration during isovolumic acceleration were measured at rest and with in-
cremental heart rate (HR). The relationship with increasing HR was evaluated for each parameter by plotting
the values at each stage of exercise versus HR.

Results: At rest, HR was similar between the two groups. LV ejection fraction and fractional shortening were
within the normal range in the CoA group. LV lateral wall and basal septal s0 and e0 velocities did not differ be-
tween the two groups, but isovolumic acceleration values were significantly lower in the CoA group. At peak
exercise, HR was similar between the groups, but all Doppler tissue imaging parameters were lower in patients
than in control subjects. When assessing the increase of each parameter versus HR, the increase in slope was
significantly lower in patients than in control subjects for LV lateral wall Doppler tissue imaging s0 and e0 veloc-
ities, and septal e0 velocity, but not for septal s0 . The relationship of isovolumic acceleration with HR was signif-
icantly reduced in the CoA group.

Conclusion: The results of this study demonstrate reduced systolic and diastolic myocardial reserve in patients
with CoA compared with control subjects. An abnormal myocardial contractile response to exercise was also
found, as shown by an abnormal LV force-frequency relationship in patients with stented CoA. The prognostic
clinical implications require further study. (J Am Soc Echocardiogr 2016;29:237-46.)

Keywords: Coarctation of the aorta, Endovascular stent, Echocardiography, Isovolumic acceleration, Exer-
cise, Force-frequency relationship

Coarctation of the aorta (CoA) is a common lesion, accounting for
5% to 8% of all congenital heart defects.1 Symptomatic neonates
are treated surgically, with good outcomes.2 For children diagnosed
beyond the newborn period (>3 months), balloon angioplasty and,
in older children, stent implantation have evolved as treatment mo-
dalities with favorable short- and intermediate-term outcomes.3-6
From the Department of Pediatrics, Division of Cardiology, The Labatt Family
Heart Centre, The Hospital for Sick Children, University of Toronto School of
Medicine, Toronto, Ontario, Canada (C.K.C., B.C., G.J.M., T.S., C.S., W.H.,
T.J.B., C.M., B.W.M., A.N.R., L.N.B., L.M.).
Reprint requests: Luc Mertens, MD, PhD, The Labatt Family Heart Centre, The
Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada
(E-mail: luc.mertens@sickkids.ca).
0894-7317/$36.00
Copyright 2016 by the American Society of Echocardiography.
http://dx.doi.org/10.1016/j.echo.2015.11.017
Despite successful initial surgical or percutaneous management,
CoA is a chronic condition with long-term morbidities related to re-
sidual arch obstruction, recoarctation, arterial hypertension, early cor-
onary artery disease, and heart failure.7-9 Endovascular stenting is
used primarily to treat native or residual CoA in older children and
adults.3-5 Because of the late diagnosis or residual or recurrent
aortic narrowing, the left ventricle in this patient group has been
exposed to a prolonged increased pressure loading, which increases
the risk for developing left ventricular (LV) dysfunction. In an earlier
study, we evaluated the effect of stent implantation on blood
pressure (BP) and LV hypertrophy and function at rest,10 and we
demonstrated preserved or increased LV ejection fraction (LVEF) at
rest. In the present study, we wanted to explore the hemodynamic
and LV myocardial response to exercise in the same patient cohort.
We hypothesized that the LV myocardial systolic and diastolic
response would be reduced because of subclinical myocardial dam-
age related to chronic pressure loading. Doppler tissue imaging
237

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238 Chen et al Journal of the American Society of Echocardiography
March 2016

Abbreviations
(DTI) and strain imaging have modified Bruce protocol. The ergometer resistance was increased by
been used to study myocardial 20 Wevery 3 min in subjects #14 years of age and by 25 W in subjects
BP = Blood pressure response to exercise in patients >14 years of age. The test was interrupted either for symptoms (fatigue,
CoA = Coarctation of the with congenital heart disease.11 chest pain, electrocardiographic changes) or when the target HR
aorta The aim of this study was to eval- (80% of the maximal HR for age) was reached. During exercise, im-
uate the LV myocardial response ages were recorded at every 10 to 15 beat/min increase in HR while
DTI = Doppler tissue imaging to exercise as measured by DTI pedaling. At each stage, image loops of $10 beats were captured to
FS = Fractional shortening in young patients after stent ensure sufficient images for offline analysis. During exercise, peak gra-
implantation for CoA using semi- dients were also recorded through the stent using a continuous-wave
HR = Heart rate
supine bicycle exercise stress Doppler technique.
IQR = Interquartile range echocardiography.
IVA = Isovolumic acceleration Echocardiographic Acquisition and Analysis
LV = Left ventricular Echocardiography was performed using a Vivid 7 echocardio-
METHODS graphic system (GE Medical Systems, Milwaukee, WI). A full resting
LVEF = Left ventricular
ejection fraction echocardiographic examination was performed before semisupine bi-
This was a single-center, pro- cycle exercise stress echocardiography using a standard clinical proto-
LVMi = Index left ventricular spective, cross-sectional study of col, in accordance with published guidelines.13 At rest and peak
mass patients who had undergone stent exercise, peak flow velocity across the aortic stent was measured
implantation for CoA during child- from continuous-wave Doppler recorded from the suprasternal
naCoA = Native coarctation
hood. A search of the cardiac inter- view. Pulsed-wave Doppler was used to evaluate flow velocity just
of the aorta
ventional database at the Hospital proximal to the aortic stent. The corrected flow velocity across the
reCoA = Recurrent for Sick Children was performed
coarctation of the aorta
aortic stent was obtained by subtracting proximal velocity from the
to identify patients who had un- peak flow velocity across the stent.14 At each stage of exercise, we ob-
SBP = Systolic blood dergone stent implantation for tained color Doppler images of the LV lateral wall and the interven-
pressure CoA at <18 years of age, between tricular septum from the apical four-chamber view. To optimize
September 1995 and November frame rates, the sector was narrowed for each wall. For all views, at
2009. Indications for stent implan- least three complete cardiac cycles were recorded and stored in
tation were a cuff systolic arm-to-leg BP gradient > 20 mm Hg in addi- raw Digital Imaging and Communications in Medicine format for
tion to an angiographically confirmed lesion, either recurrent CoA off-line analysis.
(reCoA) or native CoA (naCoA), in the isthmus region of the aorta. Resting and exercise echocardiographic parameters were analyzed
Procedural success was defined using an arm-to-leg systolic BP offline using EchoPAC software (GE Medical Systems). All conven-
(SBP) gradient # 20 mm Hg, a normal abdominal aortic pulse tional systolic and diastolic parameters were measured according to
Doppler flow profile, and a Doppler pressure gradient # 20 mm Hg published guidelines.13 Fractional shortening (FS) was measured
across the aortic isthmus. Once written consent was obtained, patients from the parasternal short-axis view by M-mode imaging. LVEF was
were recruited to participate in the study, which included clinical and determined using the biplane Simpson method. Indexed LV mass
echocardiographic assessment, 24-hour ambulatory BP monitoring,
(LVMi) was determined using the Devereux formula.15 Color DTI
and semisupine bicycle exercise stress echocardiography. was performed using a 5-mm sample volume placed in the middle
The findings obtained in patients with CoA were compared with of the myocardium at the basal third of the LV free wall and basal
those from age- and gender-matched control subjects. Control sub-
septum. During analysis, manual tissue tracking was used to ensure
jects were selected from those with normal results on echocardio-
that the sample volume remained within the myocardium throughout
graphic studies performed for the evaluation of a heart murmur, the cardiac cycle. The resulting Doppler spectral trace was displayed,
chest pain, palpitations, and/or syncope or from healthy volunteers.
and data points were smoothed with a three-sample average. Peak
The institutional research ethics board approved the study.
systolic and early diastolic DTI velocities were measured at each stage
of exercise. Fusion of the e0 and a0 waves was frequently seen during
Clinical Data exercise, and this fused wave was measured as e0 . Velocity measure-
At the time of study, the ages, gender, heights, and weights of all par- ments were recorded as the average value from three consecutive car-
ticipants were recorded. Resting heart rate (HR) and BP and resting diac cycles. Isovolumic acceleration (IVA) was obtained as described
arm-to-leg BP were measured. BP was measured with a GE previously16 (Figure 1). At each HR, three measurements of IVA
Dinamap ProCare system (Critikon, Tampa, FL); resting BP was re- were made, and an average was recorded.
corded as an average of two readings taken from the right arm while At rest, LV longitudinal strain measurements were performed us-
sitting, over a 5- to 10-min period before exercise echocardiography. ing 2D speckle-tracking echocardiography. The result was presented
Hypertension was defined as resting SBP or diastolic BP > 95th percen- as a global value of LV longitudinal strain, defined as the arithmetic
tile for gender and height in pediatric patients (<18 years of age)12 and mean value of segmental longitudinal strain indices obtained in the
SBP $ 140 mm Hg or diastolic BP $ 90 mm Hg in adults ($18 years basal, mid, and apical segments of septal and lateral walls of the
of age). All participants had clinically palpable femoral pulses. left ventricle.

Semisupine Bicycle Ergometry Reproducibility

Semisupine bicycle exercise stress echocardiography was performed To assess interobserver variability, two observers independently
on a cycle ergometer (Lode BV, Groningen, The Netherlands) using a performed offline analysis of exercise echocardiographic parameters

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Journal of the American Society of Echocardiography Chen et al 239
Volume 29 Number 3

Figure 1 Simultaneous tissue Doppler and LV pressure tracings depicting measurement of IVA. The vertical line describes the onset
of IVA, which coincides with the initial upstroke of LV pressure and the R wave on the electrocardiogram. IVA was calculated as the
difference between baseline and peak velocity divided by their time interval.

in 15 randomly selected participants. To assess intraobserver vari- formed with a commercially available package, SAS version 9.3
ability, the primary observer performed repeated measures of echo- (SAS Institute Inc, Cary, NC).
cardiographic parameters during exercise at each HR in these 15
studies 2 weeks after the first analysis.
RESULTS
Statistical Analysis
Clinical Data
Descriptive statistics of continuous data are presented as
Baseline characteristics of the two groups are summarized in Table 1.
mean 6 SD, median (interquartile range [IQR]), or minimum and
The mean age was 17.8 6 4.9 years; there was a male predominance
maximum values, as appropriate. Comparisons between control sub-
of 87%. The mean age at initial stent implantation was
jects and patients with coarctation, between those with naCoA and
12.4 6 3.5 years. The median follow-up duration (time from initial
reCoA, and between hypertensive and normotensive patients were
stent implantation to date of study) was 5.9 years (IQR, 1.6–7.0 years).
evaluated using unpaired Student’s t tests assuming unequal variance
After the initial stent implantation, five patients (17%) required addi-
between samples and Fisher exact c2 tests. Correlations between
tional interventions: balloon dilatation of the stent (n = 3) and addi-
LVMi and other baseline exercise measurements were calculated us-
tional stent implantation (n = 2). The median time from the latest
ing linear Pearson correlation. Exercise parameters, including LV
intervention to the study was 2.7 years (IQR, 1.2–6.3 years).
lateral s0 and e0 , septal s0 and e0 , and IVA, were plotted against HR
Two patients had hemodynamically insignificant intracardiac ab-
in regression models adjusted for repeated measures through an au-
normalities (one patient had a repaired ventricular septal defect
toregressive covariance structure. All exercise parameters were
with no residual lesion, and the other had a parachute mitral valve
modeled in a linear manner, while IVA was modeled as an exponen-
with no mitral stenosis or regurgitation) considered not to influence
tial function; these models were selected because they provided the
the study, along with 14 patients (47%) with bicuspid aortic valves
best fit to the data. In addition, IVA was plotted against HR to
that were not stenotic or regurgitant.
construct force-frequency curves for each individual. Slope of change
of times was compared between control subjects and patients with
CoA. Intraclass correlation coefficients were calculated for interob- reCoA versus naCoA
server and intraobserver variability. A confidence level of P < .05 Eleven patients (37%) had reCoA and underwent initial surgical
was considered statistically significant. Statistical analysis was per- repair at a median age of 1 month (range, 10 days to 6.7 years).

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240 Chen et al Journal of the American Society of Echocardiography
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Table 1 Patient characteristics (n = 30)

Control group Coarctation group reCoA group naCoA group

Variable n = 30 n = 30 P n = 11 n = 19 P

Height (cm) 167.8 6 13.0 167.4 6 14.0 .91 170.1 6 13.0 165.8 6 14.7 .42
Weight (kg) 61.6 6 15.9 68.9 6 17.1 .09 72.6 6 16.3 66.7 6 17.6 .37
BSA (m2) 1.69 6 0.28 1.78 6 0.29 .20 1.85 6 0.27 1.74 6 0.30 .35
Gender
Female 4 (13%) 4 (13%) 1 (9%) 3 (16%)
Male 26 (87%) 26 (87%) 10 (91%) 16 (84%)
Age at study (y) 17.7 6 5.3 17.8 6 4.9 .93 18.5 6 5.1 17.4 6 5.1 .60
Age at stent implantation (y) 12.4 6 3.5 13.9 6 2.9 11.5 6 3.5 .05
Duration of follow-up (y) 5.9 (1.6–7.0) 1.7 (0.4–7.2) 6.0 (4.1–7.0) .43
Resting HR (beats/min) 65 6 11 65 6 10 .89 66 6 11 64 6 10 .64
Resting RA SBP (mm Hg) 109 6 10 119 6 15 .01 120 6 18 117 6 13 .72
Resting arm-leg SBP gradient (mm Hg) 1 (0–9) 0 (0–1) 6 (0–12) .09
Resting arm-leg SBP gradient $ 20 mm Hg 4 (13%) 1 (9%) 3 (16%)
24-hr mean ABPM SBP (mm Hg) 127 6 12 127 6 14 126 6 11 .81
MASBP > 95th percentile 13 (43%) 5 (45%) 8 (42%)
Hypertensive load (%) 39 6 27 41 6 33 38 6 25 .82
BP load > 40 mm Hg 13 (43%) 5 (45%) 8 (42%)
Associated CHD
Bicuspid aortic valve 14 (47%) 5 (45%) 9 (47%)
Others* 2 (7%) 2 (18%) 0 (0%)
†
Medications 3 (10%) 1 (9%) 2 (11%)
ABPM, Ambulatory blood pressure monitoring; BSA, body surface area; CHD, congenital heart defects; MASBP, mean ambulatory SBP; RA, right
arm.
Data are expressed as mean 6 SD, as number (percentage), or as median (IQR).
*Subvalvar pulmonary stenosis and ventricular septal defect, status post ventricular septal defect repair (previous pulmonary artery banding), para-
chute mitral valve (mitral inflow mean gradient 2 mm Hg).
†
Atenolol.

Repair was by subclavian flap in six (55%), end-to-end anastomosis in
two (18%), and patch aortoplasty in three (27%). Because of residual
arch obstruction, these patients underwent stent implantation at a
mean age of 13.9 6 2.9 years. The 19 patients (63%) with naCoA un-
derwent stent implantation, at a mean age of 11.5 6 3.5 years. There
were no significant differences in demographics or clinical character-
istics between those with naCoA and those with reCoA. There was,
however, a trend toward younger age at stent implantation in the
naCoA group.
Echocardiographic Data
Resting Echocardiographic Parameters. Resting echocardio-
graphic parameters are presented in Tables 2 and 3. Average resting
gradient (corrected) across the aortic stent was 24 6 11 mm Hg.
Sixteen patients (53%) had resting gradients > 20 mm Hg (mean,
33 6 7 mm Hg), with only three having resting arm-to-leg SBP
gradients > 20 mm Hg (range, 22–30 mm Hg).
There was significantly increased LV wall thickness and LVMi in the
CoA group. LVMi was positively correlated with resting SBP (r = 0.52,
P = .003), mean ambulatory SBP (r = 0.41, P = .02), and peak exercise
SBP (r = 0.46, P = .009). LV wall thickness and LVMi did not differ
between the reCoA and naCoA groups, but LV mass Z scores were
higher in the hypertensive group than the normotensive subgroup
(median, 1.47 [IQR, 0.36 to 1.94] vs 0.06 [IQR, 0.54 to 1.06],
P = .01). FS was higher in the CoA group, while LVEF was not different
from that in normal control subjects. HR was similar between the two
groups. LV DTI systolic and diastolic velocities and LV global longitu-
dinal strain values were similar between the two groups. DTI LV lateral
s0 was significantly lower in the reCoA group compared with the
naCoA group and in hypertensive patients compared with normoten-
sive patients. Significantly lower resting IVA values were found in the
CoA group compared with control subjects (Figure 2A). Resting IVA
in hypertensive patients was lower than in normotensive patients
(0.71 6 0.26 vs 0.94 6 0.29 m/sec2, P = .04).
Among parameters used to evaluate diastolic function, mitral E-
and A-wave velocities, E-wave deceleration time, and pulmonary
vein S wave were significantly higher in the CoA group; mitral inflow
E/A ratio was lower in the study group compared with control sub-
jects (Table 2). The differences in diastolic parameters between hyper-
tensive and normotensive patients as well as between patients with
reCoA and those with naCoA were not statistically significant.
Exercise Echocardiographic Parameters. Adequate data
could be obtained over successive HR increases to determine the

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Table 2 Baseline conventional echocardiographic measurements

Control group Coarctation group reCoA group naCoA group

Variable n = 30 n = 30 P n = 11 n = 19 P

LV FS (%) 37 6 5 42 6 6 .002 39 6 3 43 6 7 .09

LVEF (%) 62 6 5 64 6 7 .12 63 6 7 65 6 7 .29
VCFC (circ/sec) 1.15 6 0.14 1.26 6 0.20 .02 1.18 6 0.18 1.31 6 0.20 .08
LVPWd (cm) 0.69 6 0.13 0.81 6 0.15 .004 0.84 6 0.09 0.80 6 0.17 .37
LVPWd Z score 0.15 (1.08 to 0.67) 0.55 (0.10 to 1.30) .004 0.55 (0.28 to 1.23) 0.50 (0.43 to 1.3) .43
IVSd (cm) 0.76 6 0.15 0.87 6 0.21 .03 0.87 6 0.24 0.86 6 0.19 .92
IVSd Z score 0.20 (0.8 to 1.20) 1 (0.15 to 2.03) .04 0.80 (0.45 to 1.95) 1.17 (0.20 to 1.96) .94
LVEDd (cm) 4.87 6 0.46 5.31 6 0.62 .004 5.49 6 0.75 5.20 6 0.53 .29
LVEDd Z score 0.20 (0.60 to 0.68) 1 (0.13 to 1.95) .02 1.40 (0.63 to 2.05) 0.80 (0.175 to 1.69) .56
RWT 0.29 6 0.05 0.31 6 0.05 .17 0.31 6 0.05 0.31 6 0.05 .77
LVM (g) 118.1 6 34.4 192.8 6 73.9 <.001 208.6 6 71.9 183.9 6 75.6 .40
LVMi (g/m2) 68.9 6 13.9 105.3 6 31.4 <.001 110.1 6 30.9 102.6 6 32.2 .55
LVM e score 1.17 (2.03 to 0.38) 0.46 (0.35 to 1.40) <.001 0.15 (0.29 to 1.59) 0.49 (0.31 to 1.35) .65
MV E (cm/sc) 99 6 17 118 6 22 <.001 116 6 26 119 6 21 .72
MV A (cm/sec) 41 6 11 57 6 15 <.001 57 6 18 57 6 14 .99
MV E/A ratio 2.61 6 0.79 2.18 6 0.65 .03 2.15 6 0.66 2.21 6 0.67 .81
DT (msec) 156 6 21 185 6 60 .02 179 6 45 189 6 69 .68
IVRT (msec) 76 6 9 77 6 8 .84 80 6 9 75 6 7 .11
PV S (cm/sec) 40 6 12 50 6 13 .003 54 6 15 48 6 12 .23
PV D (cm/sec) 61 6 13 62 6 13 .74 62 6 13 62 6 13 .88
PV Ar (cm/sec) 23 6 19 28 6 8 .35 27 6 5 28 6 9 .82
PV Ar duration (msec) 107 6 41 115 6 23 .49 115 6 19 115 6 26 .99
PV ArD  MV AD (msec) 10 (21 to 2) 17 (46 to 6) .53 9 (56 to 5) 17 (45 to 6.5) .70
PV Ar/MV A 0.60 6 0.51 0.50 6 0.16 .48 0.49 6 0.16 0.51 6 0.17 .83
Resting stent gradient (mm Hg)* 24 6 11 27 6 10 23 6 11 .38
DT, E-wave deceleration time; IVRT, isovolumic relaxation time; IVSd, interventricular septal thickness in diastole; LVEDd, LV end-diastolic dimen-
sion; LVM, LV mass; LVPWd, LV posterior wall thickness in diastole; MV, mitral valve; PV, pulmonary vein; PV ArD, duration of PV Ar wave; RWT,
relative wall thickness ([2  LVPWd]/LVEDd); VCFC, corrected mean circumferential fiber shortening.
Data are expressed as mean 6 SD or as median (IQR).
*Gradient across aortic stent at rest, corrected for flow velocity proximal to stent.

HR-related changes in LV IVA and in DTI s0 and e0 velocities in
28 of 30 patients. In two subjects, inadequate echocardiographic
windows during exercise, attributable to body habitus and respira-
tory and chest movement artifacts, impeded analysis. These
two patients were excluded from exercise echocardiographic
analysis. The remaining 28 subjects were all able to mount an effec-
tive HR response to exercise (increasing from 65 6 10 to
159 6 18 beats/min).
Peak exercise data are summarized in Table 4. HR was similar
between the two groups. Peak exercise SBP was higher in the
CoA group than in control subjects. Peak SBP was higher in the
CoA group than in control subjects. Peak Doppler systolic gradient
through the stent was 65 6 19 mm Hg, with no significantly
different between patients with reCoA and those with naCoA
or between hypertensive and normotensive patients. TDI LV
lateral wall systolic and diastolic velocities were lower in the
CoA group than in control subjects. Also, LV IVA was significantly
reduced in patients with CoA compared with control subjects
(Figure 2B). The same DTI parameters did not differ between
the reCoA and naCoA groups or between hypertensive versus
normotensive patients.
When assessing the increase of each parameter versus HR, the
slopes of increase for LV lateral wall DTI systolic and diastolic veloc-
ities and septal diastolic velocity were significantly different between
patients and control subjects. Septum systolic velocity showed a
similar increase between the two groups with increased HR
(Figure 3).
The force-frequency relationship curve, constructed by plotting
LV IVA values versus increasing HR, showed a markedly blunted
response to exercise in patients with CoA compared with control
subjects (Figure 4), with a reduced force-rate trajectory and peak
force development. The mean increase in IVA per 10 beats/min in-
crease in HR was 0.34 6 0.14 m/sec2, less than half the equivalent
increase seen in normal control subjects (0.81 6 0.18 m/sec2)
(P < .001).
Reproducibility
The intraclass correlation coefficients for intraobserver variability
were 0.98 (P < .001), 0.96 (P < .001), and 0.93 (P < .001) for intra-
observer measurements of IVA, s0 , and e0 , respectively. For

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Table 3 Baseline tissue Doppler echocardiographic and strain measurements

Control group Coarctation group reCoA group naCoA group

Variable n = 30 n = 30 P n = 11 n = 19 P

LV lateral e0 (cm/sec) 18.1 6 2.3 17.6 6 3.2 .45 18.1 6 3.9 17.3 6 2.8 .54
LV lateral a0 (cm/sec) 6.1 6 1.8 5.8 6 1.9 .59 5.4 6 1.1 6.1 6 2.2 .22
0
LV lateral s (cm/sec) 11.5 6 2.6 11.1 6 2.8 .49 9.9 6 1.7 11.8 6 3.1 .04
IVS e0 (cm/sec) 15.2 6 2.1 14.5 6 2.8 .27 14.7 6 3.1 14.4 6 2.7 .78
IVS a0 (cm/sec) 6.2 6 1.4 7.5 6 1.5 <.001 7.9 6 1.5 7.3 6 1.5 .32
IVS s0 (cm/sec) 8.7 6 0.9 9.0 6 1.7 .41 8.9 6 1.3 9.1 6 1.9 .70
LV lateral e0 /a0 ratio 3.17 6 0.83 3.23 6 1.04 .80 3.56 6 1.29 3.04 6 0.84 .25
LV e/e0 ratio 5.56 6 0.98 6.92 6 1.87 <.001 6.64 6 2.14 7.09 6 1.73 .56
IVS e0 /a0 ratio 2.56 6 0.59 1.99 6 0.49 <.001 1.95 6 0.66 2.01 6 0.38 .79
IVS e/e0 ratio 6.69 6 1.44 8.69 6 2.73 <.001 8.20 6 2.65 8.97 6 2.80 .46
LV IVA (m/sec2) 1.02 6 0.31 0.85 6 0.30 .04 0.84 6 0.29 0.86 6 0.31 .89
Global LV systolic longitudinal strain (%) 19.5 6 1.8 19.2 6 2.2 .59 18.3 6 2.1 19.8 6 2.2 .10
IVS, Interventricular septum.
Data are expressed as mean 6 SD.

Figure 2 (A) Difference in resting LV IVA values between patients with successfully stented CoA and control subjects (P = .04). (B)
Comparison of peak exercise LV IVA values between patients with successfully stented CoA and control subjects (P < .001).

interobserver variability, the coefficients were 0.94 (P < .001), 0.82
(P < .001), and 0.82 (P < .001) for the same measurements.
DISCUSSION
Although endovascular stenting has emerged as a treatment option
for CoA in selected children, with excellent short- and intermediate-
term outcomes,5,17-22 little is known of its impact on LV function. In
this study, we examined resting and dynamic LV performance during
intermediate-term follow-up of patients with reCoA and naCoA
who underwent stenting during childhood. Although most systolic
parameters were preserved at rest, we demonstrated abnormal
myocardial systolic and diastolic reserve, as well as an abnormal con-
tractile response to exercise in this patient group.
Systolic Reserve
Most studies in children after CoA repair have focused on myocardial
function at rest, although LV dysfunction is unusual in patients after
surgical repair or stent implantation, but several studies have demon-
strated abnormal exercise responses in patients with repaired
CoA.23,24 Recent studies using DTI and strain imaging have
suggested abnormal resting diastolic properties25 and reduced longi-
tudinal myocardial deformation26 in these patients, but the myocar-
dial response to exercise has not been evaluated.
Our resting data confirm the results of previous studies in patients
with postoperative CoA, demonstrating normal or even increased
systolic LV functional parameters on the basis of M-mode and
two-dimensional echocardiography.17-31 In the stented group, we
found significantly higher FS and corrected mean circumferential
fiber shortening compared with control subjects; LVEF was similar
between the 2 groups. However, the increased FS and corrected
mean circumferential fiber shortening are thought to be secondary
to the increased wall thickness and LV mass and do not accurately
represent myocardial performance.32,33 Alternative methods,
including DTI and strain imaging, have demonstrated a reduction
in LV longitudinal function early on in the disease process. This
was nicely validated in an animal study using spontaneous
hypertensive rats.34 In this model, abnormalities in myocardial me-
chanics, including reduced longitudinal, radial, and circumferential
strain and reduced early diastolic DTI velocities, occurred early in
the disease process, before the development of overt heart failure
and overt systolic dysfunction. The early changes in cardiac

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Journal of the American Society of Echocardiography Chen et al 243
Volume 29 Number 3

Table 4 Peak exercise parameters

Control group Coarctation group reCoA group naCoA group

Variable n = 28 n = 28 P n = 10 n = 18 P

Maximum HR (beats/min) 157 6 13 159 6 18 .72 162 6 19 157 6 17 .45

Peak SBP (mm Hg) 156 6 16 202 6 33 <.001 208 6 32 198 6 35 .44
Peak CoA gradient (mm Hg) — 65 6 19 — 68 6 27 63 6 14 .54
LV lateral s0 (cm/sec) 13.4 6 2.9 10.7 6 3.3 .005 10.8 6 2.9 10.6 6 3.5 .87
LV lateral e0 (cm/sec) 17.8 6 3.4 14.1 6 3.5 <.001 14.1 6 3.8 14.2 6 3.5 .95
LV IVA (m/sec2) 6.20 6 2.18 2.98 6 1.03 <.001 2.96 6 1.09 2.99 6 1.02 .48
IVS s0 (cm/sec) 11.9 6 3.3 11.3 6 2.9 .41 11.3 6 3.1 11.2 6 2.9 .91
IVS e0 (cm/sec) 16.5 6 3.8 15.6 6 2.5 .18 15.9 6 3.0 15.4 6 2.2 .63
IVS, Interventricular septum.
Data are expressed as mean 6 SD.

Figure 3 Color DTI systolic and diastolic velocities at the LV lateral wall and basal septum demonstrated that systolic and diastolic
reserve was reduced during exercise in the CoA group. All linear regression models adjusted for repeated measures through an au-
toregressive covariance structure. The difference in slopes was significantly different for LV lateral s0 (P = .003), LV lateral e0 (P < .001),
and LV septal e0 (P = .02); the slopes of LV septal s0 were not significantly different between the two groups (P = .13).

mechanics were associated with ultrastructural myocardial changes.
It is therefore important that in our patients, we did not find any
significant differences in DTI LV lateral wall s0 and septal s0 velocities,
as well as in global longitudinal LV strain between patients with CoA
and control subjects. In patients with postoperative CoA, Florianczyk
and Werner35 reported significantly higher systolic mitral annular
motion velocities and increased global longitudinal systolic strain
and strain rate compared with control subjects. These findings are
in contrast to the results of other studies.26,36,37 Lam et al.36 found
that systolic mitral annular and septal DTI velocities from 21 adults
who received endovascular stenting for CoA were significantly
lower compared with those of control subjects. Di Salvo et al.26
demonstrated reduced LV longitudinal systolic strain rate in 83
normotensive children who underwent successful repair of CoA,
in whom LVEFs were significantly higher than in control subjects.
These contradictions could be explained by differences in patient se-
lection, echocardiographic techniques used, and many other factors.
Because of the possible influence of loading conditions in the setting
of chronic pressure loading, we included IVA in our analysis. IVA has
been validated in animal models as an index of ventricular

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244 Chen et al
Figure 4 Contractile response to exercise expressed by the
force-frequency relationship curves in CoA and control groups.
Linear regression models adjusted for repeated measures
through an autoregressive covariance structure. HR was
modeled after exponential mathematical transformation. The
difference in slope was statistically significant (P < .001),
demonstrating a blunted force-frequency relationship in the
CoA group. (The individual lines represent the force-frequency
relationship curve for each study participant.)
contractile function, which correlated closely with invasive markers
of contractility, and it is relatively independent of acute changes in
loading conditions across physiologic ranges.16,38 Hence, as an
index of contractile function, LV IVA was plotted against HR to
construct the force-frequency curve for each individual subject.
One of the advantages of IVA is its ability to respond to instanta-
neous changes in force development, such as those that occur in
response to increasing HR. The force-frequency relationship is
impaired in disease states, such as dilated cardiomyopathy and ischemic
cardiomyopathy.39,40 Using this method, we have previously shown
that it is possible to measure the LV force-frequency relationship in
healthy children,41 in children after cardiopulmonary bypass,42 and
in children with univentricular circulation.43 Interestingly, we found
resting LV lateral wall IVA to be reduced in patients after stent implan-
tation, suggesting that the hypertrophic response may be associated
with depressed contractile function at rest. We also noted that hyper-
tensive patients had significantly lower resting LV lateral wall IVA
than normotensive patients, suggesting an effect of chronic pressure
loading on contractile function. This is the first study to use IVA in
the assessment of LV function in young patients who had under-
gone stent implantation for CoA. Our finding of reduced LV contrac-
tility, especially in those who were hypertensive after stenting, is
consistent with findings in adults with arterial hypertension who
were demonstrated to have impaired LV long-axis function with pre-
served overall function.44
This effect becomes even more pronounced when studying the
contractile response to exercise. Although the s0 response to exercise
seems to be preserved, the IVA response is significantly blunted. Both
maximal LV lateral wall IVA and, more important, the IVA-HR rela-
tionship are significantly blunted. Indeed, all but one of the patients
studied demonstrated significantly abnormal IVA responses to exer-
cise (Figure 4), suggesting reduced intrinsic myocardial contractility
and contractile reserve in the majority of patients. This is consistent
with experimental studies, which have shown that in subjects with
LV hypertrophy, systolic contractile response to physiologic HR in-
crease is markedly diminished; analysis of force-interval relations
suggests that abnormalities in calcium entry and reuptake probably
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Journal of the American Society of Echocardiography
March 2016
contribute to the observed systolic dysfunction.45 The reduced LV
lateral wall IVA values and blunted force-frequency relationship
are in contrast to the other indices of contractility assessed in this
study, further suggesting that IVA, particularly when measured
dynamically as part of the force-frequency relationship, may be a
more sensitive marker of myocardial contractile reserve. This may
be a very important finding for this patient population. Our study
group consisted of young patients who either had residual coarcta-
tion after surgical repair or were diagnosed with naCoA relatively
late in life. In both groups, the left ventricle was chronically pressure
loaded for a long period of time. This study demonstrates that
despite the normal parameters for systolic function at rest, myocar-
dial abnormalities can be detected during exercise. These myocardial
abnormalities could potentially be explained on the basis of
increased LV mass or elevated SBP alone, but we speculate that
this could also be a consequence of a complex adaptive response
in ventriculoarterial coupling to the presence of a stent in the de-
scending aorta, which is the focus of future work by our group.
Diastolic Function and Diastolic Response to Exercise
Arterial hypertension results in LV hypertrophy, which can cause
pathologic remodeling and myocardial fibrosis.46 Increased afterload
and LV hypertrophy can cause diastolic abnormalities. In hypertensive
patients, diastolic dysfunction can be observed even before the
appearance of LV concentric hypertrophy.47 Our findings also indi-
cate the presence of diastolic abnormalities, as evidenced by the in-
crease in mitral E velocity, the higher mitral A velocity, a prolonged
deceleration time, and a lower mitral E/A ratio compared with con-
trol subjects. No significant differences in pulmonary venous flow ve-
locities were identified, and DTI e0 velocities were not different
between the two groups. These results are consistent with those of
other studies using conventional Doppler echocardiography for the
evaluation of diastolic function after surgical repair of CoA.
Moskowitz et al.29 reported significantly lower E/A ratios in children
after repair of CoA than in healthy children. Leandro et al.30 found
higher mitral A waves and lower E/A ratios in patients with CoA
compared with control subjects. Lombardi et al.,48 in a population
of 24 children (mean age, 8.4 6 6.9 years) with isolated repaired
CoA, also found significantly higher mitral E- and A-wave velocities
and lower E/A ratios compared with control subjects. These results
suggest the presence of LV relaxation abnormality on the basis of
the mitral inflow pattern. Our baseline e0 data are not consistent
with these previous findings. Nevertheless, the observation of a signif-
icantly blunted e0 response during exercise suggests a decreased early
relaxation reserve. This is consistent with previous observations in
dogs, showing that the change in ventricular relaxation as measured
invasively by t during exercise, parallels changes in contractility
with increased HR as part of the force-frequency relationship.49
These data suggest that the decreased contractile and early relaxation
response to exercise are very strongly intertwined because of the
systolic-diastolic crosstalk. It seems intuitive that a weaker contractile
force during exercise would also affect early relaxation velocity. The
abnormal diastolic e0 response is in tandem with the decreased
force-frequency relationship and IVA response.
Study Limitations
The small number of patients in this study limits its statistical power.
Because of the short- to intermediate-term follow-up, no firm conclu-
sion could be drawn regarding the long-term impact of these findings
Journal of the American Society of Echocardiography
Volume 29 Number 3
on LV function. The patient population was a mixed one, with vari-
able time of exposure to elevated arterial hypertension. The long-
term effect and potential reversibility of the myocardial findings could
also not be studied given the current data. Some of the DTI measure-
ments may have been affected by increased translational motion of
the heart with increasing HR. We tried to correct for this by using
manual tracking to keep the sample volume in the region of interest
throughout the cardiac cycle. However, we cannot rule out
completely that there is no effect of translation on the measurement,
but we speculate the effect should be the same for patients and con-
trol subjects.
CONCLUSIONS
Patients treated with stent implantation for native or residual coarcta-
tion demonstrated a high incidence of subclinical hypertension and
LV hypertrophy, which seems to be associated with essentially normal
systolic functional parameters at rest, with some findings suggesting
mild early relaxation abnormalities. Exercise stress echocardiography
unveiled abnormal systolic and diastolic reserve, as well as a reduced
contractile response to exercise in young patients who underwent en-
dovascular stenting of CoA in childhood. The prognostic clinical im-
plications require further study.
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