Cardiopulmonary Exercise Testing in Pediatric Patients With Hypertrophic Cardiomyopathy
Exercise stress testing (EST) is clinically useful in select pediatric patients with hypertrophic cardiomyopathy (HCM). Ectopy on EST is a risk factor for cardiac death, cardiac transplant, arrhythmias requiring implantable cardioverter-defibrillator
Background
Exercise
stress testing (EST) in pediatric hypertrophic cardiomyopathy (HCM)
patients has not well described in a large heterogenous cohort.
Objectives
The objective of the study was to determine the clinical utility of EST in pediatric HCM.
Methods
This
was a retrospective single-center analysis of HCM patients younger than
21 years who had EST between January 1, 2000, and January 1, 2019.
Clinical, demographic characteristics, and EST data were analyzed, using
the last EST during the study or prior to the event in subjects with a
primary outcome. The primary composite endpoint included cardiac death,
transplant, or arrhythmia requiring implantable
cardioverter-defibrillator placement. Outcome analysis was performed
using Cox proportional hazard modeling.
Results
The
study cohort included 140 patients, 52% with a recognized genetic
variant. There were 2 tests aborted due to safety concerns (ST-segment
changes, ventricular ectopy). The median age at first EST was 13.6
years. Ninety percent of patients were tested using cycle ergometry, and
44% were on a beta-blocker. The median peak oxygen consumption was 37.1
mL/kg/min (IQR: 12.5 mL/kg/min) or 81.2% predicted, the mean anaerobic
threshold was 21.8 Ml (IQR: 8.3 mL), and the median peak power was 2.6 ±
1.1 W/kg or 73.7% predicted. Ectopy during EST was seen in 44% of
patients, and 8% had an abnormal blood pressure response to exercise.
The endpoint was reached in 12 patients. The presence of any degree of
ectopy was a predictor of the composite endpoint (hazard ratio: 5.8; 95%
CI: 1.3-26.7).
Conclusions
EST
is clinically useful in select pediatric patients with HCM. Ectopy on
EST is a risk factor for cardiac death, cardiac transplant, and
arrhythmias requiring implantable cardioverter-defibrillator.
Introduction
Hypertrophic
cardiomyopathy (HCM) is the most common inherited form of pediatric
cardiomyopathy with an incidence of 0.47 per 100,000 children1,2 and is characterized by a heterogenous collection of clinical phenotypes.3 While the majority of patients with HCM have a relatively benign course4, the disease can also be characterized by malignant arrythmias, progressive heart failure, and sudden cardiac death (SCD).5
As such, there have been several efforts to evaluate risk factors for
mortality in children with HCM, with degree of hypertrophy, unexplained
syncope, and nonsustained ventricular tachycardia all shown to be
predictive of SCD.6-9
In
the adult population, there has been a recent focus on the utility of
serial exercise stress testing (EST) in patients with HCM, with studies
showing that subnormal measures of gas exchange, including maximal
oxygen consumption (VO2) and ventilatory inefficiency, are associated with reduced survival,10-13 and the recently updated American Heart Association guidelines recommend EST as a component of the clinical evaluation.14 In children, however, EST has not been universally incorporated into the standard of care15,
and with the exception of noting the negative prognostic implications
of a failure in the ability to augment blood pressure response,7 the utility of EST in pediatric patients with HCM is largely unknown.
Thus,
the purpose of this study is to describe EST in pediatric HCM patients
performed at a single center over the course of an 18-year period, with a
focus on exercise performance compared to normative values, changes in
exercise performance with increasing age, and findings on EST predictive
of adverse cardiac outcomes.
Methods
This
study was performed with approval from the Children’s Hospital of
Philadelphia Institutional Review Board. Written informed consent was
waived owing to the retrospective nature of the study.
Cohort selection
This
was a single-center retrospective observational cohort study.
Participants were included in our study if they had a diagnosis of HCM,
underwent EST at the Children's Hospital of Philadelphia between January
1, 2000, and January 1, 2019, and were younger than 21 years at the
time of testing. The standard of care at our center is to refer all
patients with a diagnosis of HCM for EST, unless they are physically
unable to participate in testing. Potential cases were identified by
querying the Exercise Physiology Laboratory Database for patients coded
as HCM. Each participant's medical record was reviewed to confirm the
diagnosis of HCM. All patients included in this study were classified as
phenotype positive by their primary cardiologist. Patients who were
described as possible HCM, or who were genotype positive/phenotype
negative, were not included in the study cohort. Subjects meeting the
primary endpoint (defined below) prior to their first EST were excluded.
Data collection
Demographic
and clinical information was collected by manual review of the
electronic medical record, including age at HCM diagnosis and first EST,
history of genetic diagnosis, cardiac procedures and medications,
arrhythmia leading to intervention, and SCD.
Data collected from review of EST reports included maximal VO2 and VO2
at the anaerobic threshold, heart rate response, blood pressure
response, and presence of exercise-associated ectopy or ST-segment
changes during EST. The presence of any ectopic beats, either atrial or
ventricular, during warmup, exercise, or recovery was defined as ectopy.
An abnormal blood pressure response (ABPR) was defined as the failure
to augment the systolic blood pressure during exercise by at least 20 mm
Hg. Data from echocardiograms, including left ventricular ejection
fraction (EF), septal wall thickness, and left ventricular outflow tract
obstruction, were collected from clinical reports. Imaging studies
performed within 3 months prior to or 1 month after EST were included.
For those with multiple tests, descriptive statistics were captured from
either the most recent EST within the study window or the most recent
EST prior to reaching the primary outcome.
Follow-up
information through April 1, 2019, was included, as well as clinical
history preceding initial EST. Data from both inpatient and outpatient
clinical records were included.
Clinical outcome
The
primary study endpoint was a composite outcome of SCD, aborted SCD,
transplant, or ventricular arrhythmia prompting implantable
cardioverter-defibrillator (ICD) placement, with each subject limited to
a single outcome. If a patient had 2 outcomes separated in time (ie, an
aborted SCD followed by transplant), the initial event was selected as
the outcome. The components of the composite outcome were chosen based
on their similar underlying biologic mechanisms. Patients with no
follow-up visits after their first EST during the study period were
defined as lost to follow-up.
Statistical analysis
Clinical
and demographic characteristics were summarized using median (IQR) for
continuous variables and percentage for categorical variables. EST data
analysis was performed using the last EST completed within the study
window or the last test prior to the event in subjects with a primary
outcome. Percent predictive values were determined based on previously
published normative values.16
Demographics and clinical characteristics were compared between those
patients without end point reached vs those patients with end point
using t-test, Mann-Whitney U test, chi-square test, and
Fisher exact test. To describe the EST characteristic change across age,
mixed-effects regression models with fractional polynomial functions
were used adjusting for the presence of a maximum effort test, to
describe either linear or curvilinear associations.17
A total of 164 models with the dimension of the fractional polynomial
up to 3 (m = 3, chosen by the plotted data and sensitivity analysis up
to 4 dimension) were tested for each EST characteristic, and the
parsimonious polynomial models were determined by the function selection
procedure in STATA (StataCorp LLC), that is, selecting the simpler
model with the lowest Bayesian information criterion, which indicated a
better fit than other models.18,19
LOWESS (Locally Weighted Scatterplot Smoothing) plots of predicted mean
and 95% CIs across age were presented with scatter plots.
To
examine the demographic and EST characteristics associated with the
primary outcome, separate Cox proportional hazards models were used for
each characteristic. Separate models were used for EST variables due to
collinearity. Selection of candidate factors associated with the primary
outcome was determined based on clinical suspicion. Beta-blocker use
was adjusted in the Cox model of peak heart rate. The assumption of
proportional hazards over time was satisfied by testing the statistical
significance of predictors by time interaction effects in the model and
plotting the Schoenfeld residuals. Hazard ratios and 95% CIs are
presented. Kaplan-Meier analysis was used to examine the survival rates
stratified by the presence or absence of ectopy on EST. The log-rank
test was used to test the difference between survival curves.
Statistical analysis was performed using SAS version 9.4 (SAS Institute)
and STATA version 15.
Results
Demographics and clinical characteristics
Over
the 18 years studied, 140 patients with HCM who underwent at least 1
EST were identified. Seventy percent of the cohort was white (n = 98),
80% were male (n = 112), and slightly over one-half (52.1%, n = 73) had
an identified pathogenic or potentially pathogenic mutation at the time
of testing (
Supplemental Table 1). The median age of HCM diagnosis was 12.0 years, and the median age at first EST was 13.6 years
Exercise performance in HCM
This
study shows that, overall, cardiovascular fitness was impaired in this
cohort of pediatric patients with HCM and that it declines with age.
Peak VO2 represents the maximum volume of oxygen consumed by
the body and is a useful measure of cardiorespiratory fitness in a
healthy child.10,12,13,21-23 Previous studies have demonstrated impaired exercise function in adults with HCM and have shown that reduced peak VO2
is predictive of total mortality and progression to advanced heart
failure or heart transplant. In our study population, peak VO2 and power were reduced when compared to normative values, and the inverse correlation of peak VO2
and age suggests these patients have worsening exercise function as
they age. While several studies have shown that heart failure symptoms
are predictive of adverse outcomes in children with HCM,1,24
a recent risk prediction model for SCD in children with HCM did not
include heart failure symptoms in their determination of risk.25
This discrepancy may be due to the difficulty in eliciting and
identifying heart failure symptoms in children, and EST may be an
alternative method to identify previously unrecognized functional
limitations. While impaired performance on EST was not predictive of
adverse outcomes in our cohort, this may be because the study was
underpowered for relatively rare outcomes and deserves further
evaluation in a larger cohort. Aside from potential implications on
outcomes, this finding is further concerning in light of the known
correlation between reduced activity and psychosocial wellbeing26,27
and the possibility that activity restrictions have come with the
unintended consequence of increasing the cardiovascular risk profile in a
population already with risk factors in place.28-30
Risk factors identified by EST
Our
study demonstrates that EST may provide information helpful for cardiac
risk stratification for children with HCM. Ectopy of any kind,
including isolated premature atrial or ventricular contractions,
correlated with the composite outcome of SCD, transplant, or ventricular
arrhythmia prompting ICD placement; 10 of 12 children who reached the
primary outcome had ectopy on EST. While previous studies have shown
nonsustained ventricular arrhythmia as a risk factor for SCD in young
people with HCM6,25 and that, in adults, atrial fibrillation during EST predicts poor outcomes,31
our finding that exercise-induced atrial or ventricular ectopy is
associated with outcomes is a novel finding and further highlights the
utility of EST in this population. Left atrial (LA) size, a marker of
impaired diastolic function, is a known risk factor for SCD in both
children and adults. We hypothesize that atrial ectopy, which was found
to be associated with adverse outcomes, may be more commonly seen in
children with LA dilation and LA hypertension, a physiology which can be
provoked during exercise.
It is also important to note
that of the 80 patients who had no ectopy during testing, none of them
died, had SCD, or were transplanted, and only 2 of that group ultimately
had ventricular tachycardia which led to ICD placement. Thus, the
absence of ectopy on EST may help in identifying a group of patients at
lower risk.
These findings have several important
clinical implications. First, they suggest that patients with ectopy on
EST may deserve closer monitoring with more frequent outpatient
follow-up and ambulatory rhythm monitoring. Second, they suggest that
patients with no ectopy on EST may be a lower risk cohort and,
therefore, might be reasonable candidates for a shared decision-making
model for athletic participation. However, other clinical variables must
also be integrated into risk stratification in these patients.
ABPR has previously been cited as a risk factor for SCD in children7; no such predictive association was seen in our study group. Decker et al7
used treadmill testing and the modified Bruce protocol, a technique
that can make accurate assessment of blood pressure difficult. The
majority of our cohort was tested using cycle ergometry with direct
auscultation of blood pressure, which produces less artifact and, we
believe, provides a more reliable result. The findings in this study
further support the recently updated HCM guidelines which have removed
ABPR as part of the routine evaluation of SCD risk.14
Further
work evaluating the relationship between exercise capacity and
symptoms, quality of life, and outcomes in children with HCM is needed. A
better understanding could aid in the difficult process of forming
exercise guidelines, which traditionally have taken a conservative
approach despite consensus that exercise positively impacts
cardiovascular and overall health and evidence that inactivity is
prevalent in patients with HCM.27,32
If decreased aerobic capacity portends worse outcomes in these
patients, the balance of risk vs benefit regarding exercise may change.
Thus, EST may serve as an integral tool in the process of “shared
decision-making” around exercise introduced in the most recent American
Heart Association guidelines.14
Study Limitations
This
study has limitations intrinsic to retrospective analysis, and the
findings may differ from a prospectively enrolled cohort. Our study did
not include a control group. Our center is a tertiary referral center
that may see a greater portion of severe HCM, and some patients were
referred from smaller centers and thus had limited follow-up. Given that
the focus of this study was on exercise testing, not all conventional
risk factors for SCD were evaluated. The composite outcome was rare, and
the study may not be powered to detect all risk factors. As a
consequence, a multivariable analysis of risk factors for the primary
outcome could not be performed. While this study adds to the literature
on the value of EST in children with HCM, limitations exist due to the
small numbers of patients and events and the possible selection bias of
patients undergoing EST.
Conclusions
Exercise
capacity may be impaired in pediatric patients with HCM and can worsen
with age. EST is a valuable clinical tool to assess exercise capacity in
this population. Ectopy on EST is associated with the composite outcome
of SCD, cardiac transplant, and arrhythmias requiring ICD. These
findings suggest that EST is useful in the care of pediatric patient
with HCM.
,
,
,
,
,
,
,
,
,
,
,
,
,
, and
Stephen M. Paridon https://www.jacc.org/doi/10.1016/j.jacadv.2022.100107?twclid=230mzl0mfqqdxp44dhjqmeaeob
