FOCUS ISSUE: HYPERTROPHIC CARDIOMYOPATHY
Risk Factors and Mode of Death in
Isolated Hypertrophic Cardiomyopathy in Children
Jamie A. Decker, MD, Joseph W. Rossano, MD, E. O’Brian Smith, PHD, Bryan Cannon, MD,
Sarah K. Clunie, RN, BSN, Corey Gates, RN, John L. Jefferies, MD, Jeffrey J. Kim, MD,
Jack F. Price, MD, William J. Dreyer, MD, Jeffrey A. Towbin, MD, Susan W. Denfield, MD
This study was designed to review outcomes of pediatric isolated hypertrophic cardiomyopathy (HCM) managed
uniformly at a single institution and assess whether reported adult risk factors for sudden death are predictive in
Cardiac death in HCM occurs suddenly (SCD) or may be nonsudden (non-SCD). Little data exists on non-SCD in
children. Risk factors for SCD in adult HCM are characterized and consensus management strategies detailed.
Their application to children is uncertain and treatment strategies vary.
A retrospective cohort study of children with HCM was performed. Primary end points were cardiac death and
transplantation. Frequency and outcomes of known adult risk factors were assessed. Outcomes analysis was
performed using Kaplan-Meier curves and Cox regression analysis.
Ninety-six patients were included. The average age at diagnosis was 10.6 ? 5.4 years, and mean follow-up was
6.4 ? 5.2 years. Primary end points occurred in 11 patients over the 20-year follow-up (11%), 4 underwent car-
diac transplant and 7 died (3 suddenly). Extreme left ventricular hypertrophy (z-score: ?6) and an abnormal
blood pressure response to exercise were predictive of non-SCD (p ? 0.02 and p ? 0.03, respectively). Kaplan-
Meier survival analysis predicts an 82% survival over a 20-year period.
In children with isolated HCM managed primarily with exercise restriction and medication, cardiac death oc-
curred infrequently. Non-SCD or transplant was at least as common as SCD. Extreme left ventricular hypertrophy
and blunted blood pressure response to exercise were associated with an increased risk of non-SCD.
Coll Cardiol 2009;54:250–4) © 2009 by the American College of Cardiology Foundation
Patients with hypertrophic cardiomyopathy (HCM) are at
risk of death, in the form of sudden cardiac death (SCD) or
progressive heart failure (non-SCD). Previous studies have
reported that children with HCM have up to a 6% annual
mortality rate (1), although more recent data suggest the
mortality rate is closer to 1% (2,3).
Risk factors for SCD have been identified in large cohorts
of adult patients with HCM (4). Although several studies
have attempted to risk-stratify children with HCM by
identifying clinical and laboratory risk factors (3–8), most
have not been validated. Even less data exist as to risk
factors for the development of end-stage systolic and/or
diastolic heart failure in isolated pediatric HCM. Once
systolic dysfunction is noted, progression to end-stage heart
failure and death occurs rapidly (9). As limited data are
available to identify pediatric patients with HCM at risk for
cardiac death, current treatment strategies are often based
on reported risk factors for SCD in adults. As a result, no
consensus on the management of pediatric patients exists.
The purpose of this study was to review the clinical
characteristics and outcomes of our pediatric population
with isolated HCM who have been managed in a standard
manner and to determine whether reported adult risk factors
for SCD are predictive of outcome in these affected chil-
dren. In addition, we assessed progression to death and
transplant to determine if any other risk factors for cardiac
death could be identified.
Study patients. A retrospective review of patients between
January 1, 1985, and November 1, 2006, with the diagnosis
of HCM was performed through our institutional database,
From the Lillie Frank Abercrombie Section of Pediatric Cardiology, Department of
Pediatrics, Baylor College of Medicine, Houston, Texas. Dr. Decker has received
PGxHealth fellowship support from Medtronic. Dr. Cannon is a member of the
Speakers’ Bureau for St. Jude and has received PGxHealth fellowship support from
Medtronic. Dr. Jeffries is a consultant for Merck Inc. Dr. Kim is a member of the
advisory board for PGxHealth.
Manuscript received January 29, 2009; revised manuscript received March 16,
2009, accepted March 24, 2009.
Journal of the American College of Cardiology
© 2009 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 54, No. 3, 2009
including patients enrolled from our institution in the National
Institutes of Health–supported PCMR (Pediatric Cardiomy-
opathy Registry) database (2). Criteria for inclusion in the
study were age ?18 years at the time of diagnosis and
echocardiographic evidence of either concentric left ventricular
hypertrophy or asymmetric septal hypertrophy (defined as a
diastolic septal thickness or left ventricular diastolic wall thick-
ness z-score ?2) with no other cause. This study was approved
by the Baylor College of Medicine institutional review board.
Individual consent was waived.
echocardiography was performed at rest using standard methods.
Left ventricular outflow tract obstruction was defined as a peak
resting gradient ?16 mm Hg (peak velocity ?2 m/s). All studies
were read by a pediatric cardiologist.
Data collection. Demographic information and the re-
ported adult risk factors for sudden death (4), including
extreme left ventricular hypertrophy, abnormal blood pres-
sure response to exercise, history of prior cardiac arrest or
sustained ventricular tachycardia, documented nonsustained
ventricular tachycardia, non-neurocardiogenic syncope, and
a family history of HCM with associated sudden death were
collected. In addition, left ventricular posterior wall and
septal echocardiographic measurements, degree of left ventric-
ular outflow tract obstruction, exercise stress testing results,
Holter results, clinical symptoms,
and treatment strategies, including
or implantable cardioverter-defi-
brillator (ICD) placement, septal
myectomy, and cardiac transplan-
tation were also collected.
Exercise testing. Exercise testing
was performed on a Marquette
pediatric treadmill (Marquette
Electronics, Milwaukee, Wiscon-
sin), using a standard or modified
a manual sphygmomanometer in the upper extremities during
testing. An abnormal blood pressure response to exercise was
defined as either a hypotensive response or a minimal increase in
the systolic blood pressure to increased workload compared with
baseline (?20 mm Hg). Continuous electrocardiograms were
recorded in all cases. Peak oxygen consumption was measured
Management algorithm. Patients diagnosed with HCM
were evaluated in the Cardiomyopathy Clinic. The man-
agement strategy is outlined in Figure 1. Some patients had
multiple clinical characteristics that fell into more than 1
category in the management algorithm.
HCM ? hypertrophic
ICD ? implantable
RSCD ? resuscitated
sudden cardiac death
SCD ? sudden cardiac
Figure 1Texas Children’s Hospital Management Algorithm for HCM
Schematic approach to treatment of pediatric hypertrophic cardiomyopathy (HCM). ICD ? implantable
cardioverter-defibrillator; LVOTO ? left ventricular outflow tract obstruction; PHT ? pulmonary hypertension; SCD ? sudden cardiac death.
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Decker et al.
Statistics. Death and cardiac transplantation were the primary
end points. Statistical analysis was performed using SPSS for
Windows version 16.0 (SPSS, Inc., Chicago, Illinois). Clinical
variables were converted into groups and univariate analysis
using the log-rank test was performed. Kaplan-Meier survival
curves were generated. Individual z-score measurements were
run in Kaplan-Meier survival analysis to determine a statisti-
cally significant z-score. Cox regression analysis was used to
perform univariate analysis. Baseline data were reported as a
mean ? 2 SD, or a median with an interquartile range.
Statistical significance was taken as p ? 0.05. No adjustments
were made for a type I error.
A total of 426 patients were diagnosed with hypertrophic
cardiomyopathy between January 1, 1985, and November 1,
2006. Ninety-six patients met inclusion criteria for isolated
HCM. Clinical characteristics of the patient population are
listed in Table 1. Sixteen patients had a hemodynamic
assessment in the cardiac catheterization laboratory due to
noninvasive assessments suggesting restrictive physiology or
pulmonary hypertension. Eight of these patients had pul-
monary hypertension (average pulmonary artery mean pres-
sure: 34.1 ? 8.4 mm Hg), all of whom had an elevated
end-diastolic ventricular pressure consistent with restrictive
physiology (average: 23 ? 7.3 mm Hg). Three patients had
an elevated end-diastolic ventricular pressure (average end-
diastolic ventricular pressure: 21.3 ? 6.1 mm Hg) without
Symptoms. One patient presented with symptomatic heart
failure due to systolic dysfunction. The reason for the
diagnostic echocardiogram in the other patients is listed in
Table 1. The presenting symptom was not documented in the
medical record in 9 (9%) patients. Twenty-seven patients
(28%) remained asymptomatic throughout follow-up. The
remaining 69 patients complained of chest pain, fatigue,
dyspnea on exertion, palpitations, or a combination of these
during follow-up. No single symptom or constellation of
symptoms was a risk factor for cardiac death.
Adult risk factors for SCD. The frequency of reported
adult risk factors for SCD is summarized in Table 2. No
single or multiple risk factors were predictive of SCD.
However, a left ventricular wall thickness z-score ?6 and an
abnormal response to exercise were predictive of non-SCD.
Arrhythmias. Seventeen patients had arrhythmias. Five
children had atrial tachyarrhythmias and 12 had ventricular
tachyarrhythmias. The presence of any arrhythmias, includ-
ing nonsustained ventricular tachycardia on Holter monitor
was not significant for cardiac death.
Resuscitated sudden cardiac death (RSCD). Of the 7
patients with an RSCD event, the average age at diagnosis of
HCM was 10.3 ? 4.9 years. The rhythm at the time of the
arrest was documented in 4 patients, 2 of whom had ventric-
Table 1Patient Characteristics
Demographic data, n (%)
Female 30 (31)
Caucasian 51 (53)
Hispanic 22 (23)
African American17 (18)
Age at diagnosis
Cohort mean, yrs, ? 2 SD 10.6 ? 5.4
Cohort median, yrs (IQR)12.2 (7.8–14.8)
Age ?1 yr, n (%) 10 (10)
Age ?1 and ?5 yrs, n (%)8 (8)
Age ?5 and ?10 yrs, n (%) 19 (20)
Age ?10 and ?18 yrs, n (%) 59 (62)
Family history, n (%)
HCM-related sudden death16 (17)
Presenting sign/symptom, n (%)
Murmur 43 (45)
Family history of HCM18 (19)
Chest pain 7 (7)
Dyspnea on exertion4 (4)
Resuscitated sudden death 4 (4)
Palpitations 1 (1)
Heart failure 1 (1)
Mean ? 2 SD6.4 ? 5.2
Median (IQR)5 (1 month to 24 yrs)
Death/cardiac transplant, n (%)11 (11)
Left ventricular morphology, n (%)
Asymmetric septal hypertrophy 68 (71)
Concentric left ventricular hypertrophy 28 (29)
Septal wall z-score in diastole
Mean ? 2 SD 4.2 ? 2.3
Median (IQR) 4.3 (2.5–5.9)
Posterior wall z-score in diastole
Mean ? 2 SD 2.2 ? 2.6
Median (IQR)2.2 (0.5–3.7)
Fractional shortening (n ? 90)*
Mean ? 2 SD 46 ? 8.8
Median (IQR) 45 (40–51)
*Quantitative echocardiographic functional analysis not available in all patients.
HCM ? hypertrophic cardiomyopathy; IQR ? interquartile range.
Prevalence of Adult Risk Factors of Sudden Death
Table 2Prevalence of Adult Risk Factors of Sudden Death
(Overall % of Patients)
(n ? 85)
(n ? 11)p Value*
Syncope (18%) 1430.57
Family history of premature
HCM-related death (22%)
Nonsustained VT (10%)910.76
Prior cardiac arrest (6%)610.92
Extreme LVH (z-score ?6) (24%)176
Left ventricular outflow tract
Inappropriate BP response to
*Log-rank test; †58% of total patients underwent exercise testing.
BP ? blood pressure; HCM ? hypertrophic cardiomyopathy; LVH ? left ventricular hypertrophy;
VT ? ventricular tachycardia.
252Decker et al.
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ular tachycardia and 1 had ventricular fibrillation. One patient
with an ICD discharge had ventricular tachycardia. This was
the presenting symptom in 4 patients. The 3 patients with a
prior diagnosis of HCM were engaged in restricted physical
activity at the time of the arrest. The average septal diastolic
wall thickness z-score of this group was 4.9 ? 3.8 and the
average posterior wall thickness z-score was 2.19 ? 1.5.
Echocardiographic analysis. The echocardiographic char-
acteristics of the patient population are summarized in Table 1.
Twenty-three patients (27%) had severe hypertrophy with a
diastolic left ventricular posterior wall or diastolic septal wall
thickness z-score ?6. This included 2 patients who underwent
heart transplantation and 4 who died. A left ventricular
diastolic wall thickness z-score ?6 predicted cardiac
death (p ? 0.02) (Fig. 2A). The calculated hazard ratio of
cardiac death was 3.8 (95% confidence interval: 1.1 to 12.5).
Two patients who died had qualitatively severely depressed left
ventricular systolic function. One additional patient had de-
pressed systolic function before transplantation. The presence,
degree, or absence of left ventricular outflow tract obstruction
did not predict cardiac death.
Exercise testing. Fifty-six patients had at least 1 exercise
treadmill test. Nineteen (34%) had an abnormal blood pressure
response to exercise. Of those undergoing exercise testing, 48
blocker therapy, comprising 95% of those tested. Despite these
medications, 37 (66%) had a normal blood pressure response to
exercise. An abnormal blood pressure response to exercise was a
risk factor for cardiac death (p ? 0.03) (Fig. 2B). The calculated
hazard ratio for cardiac death if there was an abnormal blood
ICDs. Seventeen patients received ICDs (Fig. 1). The mean
follow-up time after implantation was 3.6 ? 2.1 years. One
patient, who had an ICD placed for a history of ventricular
tachycardia and syncope, had 2 appropriate discharges for
ventricular tachycardia and 2 inappropriate discharges for atrial
tachycardia/fibrillation. This patient was not included in the
end point analysis as this patient was conscious and this was
considered the same as an RSCD event. Two other patients
underwent cardiac transplantation after ICD placement due to
persistent heart failure symptoms.
Outcomes. Over the 21-year period, there were 11 cardiac
deaths, which consisted of 7 deaths and 4 cardiac transplan-
tations. Of the patient deaths, 3 had sudden cardiac death
and 3 had non-SCD (2 from systolic heart failure, 1 from a
massive stroke). One cause of death was unknown. Of the
transplanted patients, 3 (75%) had elevated end-diastolic
pressures and 2 had pulmonary hypertension measured by
cardiac catheterization. All had intractable heart failure symp-
toms, most commonly chest pain, fatigue, and dyspnea on
exertion. One patient had systolic dysfunction at the time of
transplantation. Kaplan-Meier survival analysis shows an 82%
survival for the entire group at 21 years (Fig. 3).
Predicting which patients with HCM are at greatest risk of
sudden cardiac death has been the major focus of investi-
gation in adults and children. Risk factors in adult studies
are well described. Studies have been inconsistent in chil-
dren, which may reflect the varying etiologies of HCM
(2,3,5,7,8), as well as the low incidence of cardiac death (2),
also noted in this study. Prior studies have documented the
importance of non-SCD in infants ?1 year of age (2).
However, in older children, other modes of death are not well
documented. In this study, non-SCD was more common than
SCD in children. Therefore, although none of the previously
identified adult risk factors predicted SCD in our pediatric
cohort, the identification of risk factors for non-SCD is at least
as important in children as identifying risk factors for SCD.
Figure 2 Risk Factors for Cardiac Death
Kaplan-Meier survival analysis for left ventricular wall thickness (A) and blood pressure response to exercise (B).
JACC Vol. 54, No. 3, 2009
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Decker et al.
One risk factor was extreme left ventricular hypertrophy,
which is defined in adult studies as an absolute left ventric-
ular wall thickness of 30 mm (4). Absolute values in children
are not as useful due to changing body surface area. This
study is the first to show a significant association between
left ventricular wall thickness indexed to body surface area,
defined as a z-score ?6, and premature death or transplan-
tation in children with isolated HCM.
The second risk factor predictive of cardiac death in
children was an abnormal blood pressure response to exer-
cise. Although the majority of children were on a potentially
blood pressure-lowering agent, 66% still maintained a nor-
mal blood pressure response. Children with a blunted blood
pressure response to exercise or a hypotensive response to
exercise had a higher incidence of cardiac death.
Although both of these risk factors were predictive of
cardiac death, neither was associated with SCD. This may
be due to the small number of sudden deaths in our
population, but it may also be due to the fact that SCD or
RSCD is often a presenting symptom in children. In the 7
patients with RSCD, the event was the presenting symptom
for 4. Three patients had an RSCD event after the diagnosis
of HCM was made. All of these patients were noncompli-
ant, engaging in some form of physical activity at the time
of cardiac arrest. The low incidence of SCD seen in this
study is similar to that recently reported in the PCMR (2).
The reason for the lower incidence of sudden death in the
multicenter PCMR cohort is unknown, because manage-
ment approaches and patient compliance could not be
addressed. In our study, the low incidence of SCD after
diagnosis may be, in part, secondary to the management
strategy of exercise restriction and beta-blockade for virtu-
ally all patients, starting at the time of diagnosis, with
further treatment based on symptoms and the presence of
potential risk factors for sudden cardiac death.
Study limitations. This study is a retrospective survival
analysis and has limitations intrinsic to such an analysis.
There were a low number of cardiac deaths, and therefore
the study may not be powered to detect all risk factors. In
addition, the number of patients who underwent catheter-
ization was not enough for statistical analysis. The number
of end points was also small and limited valid multivariate
analysis. Controlled exercise testing is not possible in young
children and infants, and a blunted blood pressure response
to exercise can be normal in pre-pubescent children, making
interpretation of such data in these patients difficult.
Patients managed with our treatment algorithm demon-
strated ?80% survival over 20 years of follow-up. Cardiac
death was at least as likely to be from non-SCD as SCD.
Therefore, the ability to predict non-SCD is as important as
the ability to predict SCD. A left ventricular wall thickness
z-score ?6 and an abnormal blood pressure response to
exercise were found to be risk factors for non-SCD and
therefore warrant close follow-up and further study in a
large multicenter cohort.
Reprint requests and correspondence: Dr. Susan W. Denfield,
Lillie Frank Abercrombie Section of Pediatric Cardiology, Texas
Children’s Hospital, 6621 Fannin MC 19345-C, Houston, Texas
77030. E-mail: email@example.com.
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Key Words: pediatrics y hypertrophy y cardiomyopathy y ventricular
tachycardia y sudden cardiac death y implantable cardioverter-defibrillator.
Figure 3 Overall Survival
Kaplan-Meier survival analysis for the cumulative survival over the study period.
254Decker et al.
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