CLINICAL RESEARCH

European Heart Journal (2011) 32, 11141120

doi:10.1093/eurheartj/ehr021

Prevalence and clinical correlates

of QT prolongation in patients
with hypertrophic cardiomyopathy
Jonathan N. Johnson 1, Camilla Grifoni 2, J. Martijn Bos 3, Maha Saber-Ayad 2,
Steve R. Ommen 4, Stefano Nistri 2, Franco Cecchi 2, Iacopo Olivotto 2,
and Michael J. Ackerman 1,3,4*

Received 14 June 2010; revised 11 January 2011; accepted 24 January 2011; online publish-ahead-of-print 22 February 2011

Aims

Congenital or acquired QT prolongation is a risk factor for life-threatening arrhythmias. In patients with hypertrophic
cardiomyopathy (HCM), the QT interval may be intrinsically prolonged. However, the prevalence, cause, and significance of QT prolongation among patients with HCM are unknown.
.....................................................................................................................................................................................
Methods
After exclusion of patients on QT-prolonging drugs, a blinded, retrospective analysis of electrocardiograms, echocarand results
diograms, and genotype status in 479 unrelated patients with HCM [201 females, age at diagnosis 41 + 18 years,
maximal left ventricular wall thickness (MLVWT) 22 + 6 mm] from two independent centres was performed. The
mean QTc was 440 + 28 ms. The QTc exceeded 480 ms in 13% of patients. Age, gender, family history of HCM
or sudden cardiac arrest, and genotype status had no association with QTc. Patients with a QTc over 480 ms
were more symptomatic at diagnosis (P , 0.001), had a higher MLVWT (P 0.03), were more obstructive
(P , 0.001), and were more likely to have undergone septal reduction therapy (P 0.02). There was a weak but
significant direct linear relationship between QTc and peak outflow gradient (r 2 0.05, P , 0.0001).
.....................................................................................................................................................................................
Conclusions
Compared with ,1 in 200 otherwise healthy adults, QT prolongation (QTc . 480 ms) was present in 1 out of 8
patients with HCM. The QTc was partly reflective of the degree of cardiac hypertrophy and left ventricular
outflow tract obstruction. Because of its pro-arrhythmic potential and its potential relevance to management and
risk stratification, routine QTc assessment should be performed in patients with HCM, particularly when concomitant use of QT-prolonging medications is considered.

----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords

Long QT syndrome Hypertrophic cardiomyopathy Sudden death Ventricular arrhythmia QT interval

Introduction
Affecting 1 in 500 persons, hypertrophic cardiomyopathy (HCM)
is the most prevalent heritable cardiovascular disease and the most
common cause of sudden cardiac death in young athletes.1 Clinically, HCM is characterized by unexplained and unequivocal
cardiac hypertrophy in the absence of hypertrophy-inducing conditions such as hypertension and aortic stenosis. At the cellular
level, HCM is characterized by cardiomyocyte hypertrophy,

interstitial fibrosis, and myofibrillar disarray. To date, over 25

HCM-susceptibility genes have been implicated in the pathogenesis
of this disease.2
Besides the underlying genotypic heterogeneity, HCM is characterized by profound phenotypic heterogeneity as well. Patients can
display extremely varying degrees of hypertrophy, fibrosis, and left
ventricular outflow tract (LVOT) obstruction.1 Similarly, the clinical presentation can vary from completely asymptomatic to endstage heart failure or sudden death.3,4 Patients with HCM have

* Corresponding author Long QT Syndrome Clinic and the Mayo Clinic Windland Smith Rice Sudden Death Genomics Laboratory Mayo Clinic, Guggenheim 501, 200 First Street
SW, Rochester, MN 55905, USA. Tel: +1 507 284 0101, Fax: +1 507 284 3757, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2011. For permissions please email: [email protected].

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1
Department of Pediatrics/Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN, USA; 2Department of Cardiology, Referral Center for Myocardial Diseases, Azienda
Ospedaliera Universitaria Careggi, Florence, Italy; 3Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA; and 4Department
of Medicine/Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA

1115

QT prolongation in patients with HCM

an increased propensity for potentially life-threatening ventricular

arrhythmias. The annual risk of sudden death, while initially
reported by McKenna et al. in a selected population to be as
high as 7%, is between 0.8 and 1.2% among unselected
populations.1,5 8
Marked prolongation of the QT interval is a pro-arrhythmic
risk factor in both congenital long QT syndrome (LQTS) and
drug-induced LQTS.9 13 In addition, spontaneous or drug-induced
QT prolongation is a risk factor in patients with coronary artery
disease.14,15 While QT prolongation has been reported in small
cohorts of patients with HCM,16 18 the prevalence and clinical significance of QT prolongation among a large population of patients
with HCM is unknown.

Methods
In this Institutional Review Board-approved study, we retrospectively
reviewed the clinical records for 531 unrelated HCM patients evaluated between 1995 and 2001. Patients were seen at one of two
medical centres: (i) the Mayo Clinic Hypertrophic Cardiomyopathy
Clinic, Rochester, MN, USA, and (ii) the Referral Center for Myocardial Diseases, Azienda Ospedaliero Universitaria Careggi, Florence,
Italy. Clinical records were reviewed for age at diagnosis, cardiac symptoms at diagnosis, echocardiographic data, family history of HCM or
sudden death, presence of an implantable cardioverter defibrillator
(ICD) and/or pacemaker, and a history of surgical myectomy. Symptoms were assessed using the standard New York Heart Association
(NYHA) class system. The follow-up period was calculated as the
difference between the date of diagnosis at our institution(s) and the
last date of available follow-up. If a patient had an ICD placed,
follow-up interrogation of discharge records was performed for the
presence of appropriate ventricular fibrillation (VF)-terminating
interventions. Any patient on a potential QT-prolonging drug was
excluded from this analysis; this predominantly consisted of patients
on amiodarone, sotalol, and disopyramide. The majority of patients
were on beta-blockade at the time of referral to our institutions,
and these patients were included. After excluding patients with electrocardiographic (ECG) evidence of ventricular pacing or taking
medications with a known QT-prolonging effect (n 52), a cohort
of 479 patients remained for analysis.

Diagnosis of hypertrophic cardiomyopathy

Diagnosis of HCM was based on the echocardiographic demonstration
of a hypertrophied left ventricle (wall thickness 15 mm), associated
with a non-dilated cavity and in the absence of another cardiac or
systemic disease that could produce that magnitude of hypertrophy.

Mutational analysis
All patients had been genotyped previously for the nine most common
myofilament-associated and six Z-disc-associated HCM-susceptibility
genes, as previously described.19,20

Electrocardiographic analysis
We reviewed the first available ECG study for each patient performed
at the time of diagnosis of HCM. Electrocardiographic analysis was performed using a 12-lead ECG and the 12SL ECG analysis programme
from GE Marquette Medical Systems, or ESAOTE Organizer.
Abstracted ECG measurements included the RR, QT, JT, and QRS

Echocardiographic studies
Comprehensive two-dimensional and Doppler echocardiographic
studies were performed in each patient using commercially available
instruments at the time of diagnosis. Abstracted echocardiographic
measurements included maximum left ventricular wall thickness
(MLVWT), presence/absence of obstruction (a resting or provocable
gradient .30 mmHg was considered obstructive), and basal LVOT
gradient. Left ventricular hypertrophy (LVH) was assessed by twodimensional echocardiography, and the site and extent of maximal
wall thickness were identified. Peak instantaneous LVOT gradient, due
to mitral valve systolic anterior motion and mitral septal contact, was
estimated with continuous wave Doppler under basal conditions. The
left atrial dimension was measured at end-systole in the anteroposterior
linear diameter from the parasternal long-axis view.

Statistical analysis
All continuous variables were reported as the mean + SD. Proportions were analysed and compared using a two-tailed Z-test for
proportions. Means were analysed using a two-tailed independent
groups t-test for means. A P-value of ,0.05 was considered to be statistically significant. Linear regression models were used to correlate
QTc with continuous variables. Variables that were statistically significant in univariate models were included in a multivariate logistic
regression model to determine whether they remained significant
after adjustment for potential confounders. Population normative
ECG values were obtained using available published studies.23,24 All
analyses were conducted with the computer software JMP, version
8.0 (SAS Institute, Inc, Cary, NC, USA).

Results
Prevalence of QT prolongation
in hypertrophic cardiomyopathy
A total of 479 patients with HCM were included in the study (201
females, average age 41 + 18 years, Table 1). Patients taking medications with a known QT-prolonging effect (www.qtdrugs.org)
were excluded from the analysis. Compared with the QTc distribution reported among otherwise healthy adults23,24 (Figure 1),
there was a marked right shift in the QTc distribution in this
HCM cohort with a mean QTc of 440 + 38 ms. As seen normally,
females in our cohort had a slightly longer QTc (445 + 37 ms)
than males (437 + 38 ms; P 0.03). Compared with ,0.5% of
normals who have a QTc . 480 ms,23 62 HCM patients (13%)
had a QTc . 480 ms and 25 of these patients (5.2% of the
total) had a QTc over the pro-arrhythmic threshold of 500 ms
(Figure 1). The QTc value identifying the upper quartile for our

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Patients

intervals. All QT and RR intervals were confirmed manually. JT

values were obtained by subtracting the QRS interval from the QT
interval.21 QTc values were calculated using the standard Bazett
formula.22 JTc values were calculated using a similar rate correction
equation [JTc JT/(RR1/2)]. QT intervals were measured using leads
II or V5 when possible. The reviewers (J.N.J., C.G.) were blinded at
all times to the patients clinical history and genotype status. In
addition, the echocardiographic and ECG analyses were performed
independently to ensure a lack of bias. In patients, who had undergone
surgical myectomy or septal ablation, ECGs studied were obtained
prior to procedure or, if no pre-procedure ECG was available, patients
were excluded from analysis.

1116

Table 1

J.N. Johnson et al.

Demographic variables study cohort

Total

QTc 480 ms

QTc > 480 ms

479

417

62

Sex (male/female)
Age at diagnosis (years)

278/201
41.1 + 18

244/173
41.1 + 18

34/28
41.1 + 18

P-value*

...............................................................................................................................................................................

Mean NYHA class at diagnosis

MLVWT (mm)
LVOT gradient (mm Hg)

1.9 + 0.8

1.9 + 0.8

2.4 + 0.8

22.1 + 6
40.7 + 40

21.8 + 6
38.9 + 41

24.1 + 8
52.6 + 37

0.58
0.98
0.001
0.03
0.01

Patients w/obstruction, n (%)

233 (49)

188 (45)

45 (74)

,0.0001

QTc (ms)
JTc (ms)

440.7 + 37
327.6 + 37

431.1 + 28
323.3 + 33

505.3 + 25
357.0 + 46

,0.0001
,0.0001

108.6 + 27

104.3 + 22

137.8 + 39

,0.0001

146 (31)
82 (17)

127 (31)
71 (17)

19 (31)
11 (18)

1
0.85

Surgical myectomy, n (%)

141 (29)

117 (28)

24 (39)

0.12

Septal ablation, n (%)

Myectomy or ablation, n (%)

31 (6)
172 (36)

23 (6)
140 (34)

8 (13)
32 (52)

0.05
0.01

ICD, n (%)

90 (19)

72 (17)

18 (29)

0.04

224 (47)

201 (48)

23 (37)

0.13

MYBPC3

86 (18)

77 (18)

9 (15)

0.56

MYH7
Thin filament

80 (17)
18 (4)

72 (17)
17 (4)

8 (13)
1 (2)

0.5
0.55

Genotype positive, n (%)

Mutation location, n (%)

Z-disc

12 (3)

10 (2)

2 (3)

Multiple

28 (6)

25 (6)

3 (5)

0.94

Shown are the total demographics for the complete study cohort as well as a comparison between patients with a QTc 480 ms and a QTc . 480 ms. All values expressed at
mean + SD. Of note, Z-disc genes were not studied in the Florence cohort.
*P-value compares the difference between cohorts with a QTc 480 and QTc . 480 ms.

QTc . 480 ms, both prolongation of the JTc (357 + 46 vs.

323 + 33 ms in patients ,480 ms; P , 0.0001) and prolongation
of the QRS interval (138 + 39 vs. 104 + 22 ms; P , 0.0001) contributed to the prolonged QTc. As further confirmation, both JTc
and QRS were independently strongly correlative of having a
QTc . 480 ms in a logistic model of clinical correlative factors
(P 0.01).

Clinical correlates of QT prolongation

Figure 1 QTc-distribution in health and disease. Shown are the

distributions of normal QTc in healthy males and females as well
as the Mayo long QT syndrome cohort and the studied hypertrophic cardiomyopathy cohort. Five per cent of patients with
hypertrophic cardiomyopathy had a QTc exceeding the
pro-arrhythmic threshold of 500 ms.
HCM cohort was 461 ms. There were no differences in age, male/
female ratio, or QTc between the Mayo (n 337) and Florence
cohorts (n 142, data not shown). Among the 62 patients with

Comparing the 62 patients with a QTc . 480 ms to the rest of

the HCM cohort (Table 1), patients with a QTc . 480 ms had a
significantly higher mean NYHA class at diagnosis (2.4 + 0.8 vs.
1.9 + 0.8; P , 0.001; Figure 2A), had a higher MLVWT (24.1 + 8
vs. 21.8 + 6 mm; P 0.03; Figure 2B), were more likely to be
obstructive (74 vs. 45%; P , 0.001; Figure 2C), and were more
likely to have undergone therapeutic septal reduction therapy by
either septal ablation or surgical myectomy (52 vs. 34%; P
0.02; Figure 2D). Patients with a QTc . 480 ms were also more
likely to have a risk profile ultimately judged to require ICD for
primary or secondary sudden death prevention (29 vs. 17%; P ,
0.04). Overall, there was a significant but weak relationship
between QTc and the LVOT basal gradient (r 0.05; P ,
0.0001; Figure 3A) and maximum MLVWT (r 0.03; P 0.0002;
Figure 3B). Additionally, an increased NYHA class at diagnosis
was related to increasing QTc values (r 0.08; P , 0.0001).

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QRS (ms)
Family Hx of HCM, n (%)
Family Hx of sudden death, n (%)

QT prolongation in patients with HCM

1117

with a QTc over 480 ms were more likely to be symptomatic at diagnosis (A), had a greater maximum left ventricular wall thickness (B),
were more likely to be obstructive (C), and were more likely to have undergone septal reduction therapy by either septal ablation or surgical
myectomy (D).

Figure 3 QTc plotted against basal left ventricular outflow tract gradient (A) and the maximum left ventricular wall thickness (B). QTc
showed a weak, but significant relationship with left ventricular outflow tract gradient and maximum left ventricular wall thickness.

Conversely, family history of HCM, family history of sudden death,

age at diagnosis, and specific genotype status had no association
with the QTc duration. For the majority of patients in our
cohort (90%), the hypertrophy was concentrated at the outflow
tract or over the whole length of the septum; 10% of patients
had an apical distribution of HCM.
The 25 patients with a QTc over the pro-arrhythmic threshold
of 500 ms were significantly younger at diagnosis (34.1 + 14 years

old) compared with the remaining 37 patients (45.8 + 19 years;

P 0.008) with a QTc between 480 and 500 ms (data not
shown). Although the data trended in the same direction, no statistically significant differences were observed in the NYHA class at
diagnosis, MLVWT, number of obstructive patients, or rate of
therapeutic interventions for obstruction in these two subsets
(data not shown). Ten of these patients (40%) ultimately underwent ICD therapy for established HCM risk factors.

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Figure 2 Bar diagrams showing significant differences between the subset of patients with a QTc 480 ms and a QTc . 480 ms. Patients

1118

Patients with unexplained QT

prolongation

Relation to genotype
In the overall cohort, 53% of patients were genotype negative, while
47% of patients had an HCM-associated mutation discovered
(Table 1). Patients in the Florence cohort were more likely to have
a positive genotype (62%) compared with the Mayo cohort (40%;
P , 0.001). The QTc was significantly lower among genotypepositive patients (435 + 35 ms) when compared with genotypenegative patients (445 + 40 ms; P 0.006). The JTc was similarly
lower among genotype-positive patients (P , 0.02). Genotypenegative patients were older in age when compared with genotypepositive patients (45.3 + 18 vs. 36.5 + 27 years; P , 0.0001) and
had a smaller mean MLVWT (20.9 + 6.1 vs. 23.4 + 6.1 mm; P ,
0.0001). There was no significant difference in the rate of genotype
positivity between patients with a QTc over 480 ms (37% genotype
positive) compared with patients with a QTc under 480 ms (48%
genotype positive; P 0.1; Table 1), nor were there any differences
between the specific genetic subtypes.

Prevalence of arrhythmias and outcome

A total of 90 of 479 (19%) patients ultimately had an ICD placed
based on primary or secondary prevention of sudden cardiac
death. Fifteen of these patients received their device as secondary
prevention after out-of-hospital cardiac arrest or sustained ventricular tachycardia (Table 2). The remaining patients had an ICD placed
prophylactically based on the presence of one or more established
risk factors as listed in Table 2. It must be noted that, as not always
feasible in clinical practice, not all risk factors were universally
assessed for each patient with Holter monitor data least available
for these patients. Over a mean follow-up period of 4.9 +
3.3 years, 11 of 90 (12%) patients with an ICD had appropriate
VF-terminating device discharges; 6 of these patients had received
their ICD as secondary prevention, and 5 for primary prevention.
There were no characteristic differences in reason for ICD placement or specific risk factors between patients with a QTc under
480 ms when compared with patients with a QTc over 480 ms.

Furthermore, there was no significant difference in the rate of appropriate VF-terminating discharges between the two groups (P 0.1;
Table 2). Appropriate ICD therapies were paradoxically only seen
in the subgroup of patients with a QTc under 480 ms. Fifteen per
cent of patients with an ICD in this subgroup received appropriate
VF-terminating discharges, whereas no appropriate ICD discharges
were observed in the 18 patients with an ICD and QTc over
480 ms. There was no significant difference in phenotypic or clinical
expression of disease between patients with a QTc . 500 ms and
those with a QTc between 480 and 500 ms.
Of note, there were 12 of 90 patients (13%) who received inappropriate discharges, of whom two had a QTc .480 ms.

Discussion
Marked prolongation of the QT interval is a pro-arrhythmic risk
factor in both congenital- and drug-induced LQTS as well as in
several disease states including coronary artery disease.9 14
Herein, we describe the prevalence and patterns of QT prolongation in a large cohort of patients with HCM. The QT interval
was significantly prolonged (QTc .480 ms, or greater than
one standard deviation above the mean QTc), even without
QT-prolonging pharmacological intervention, in 13% of our
HCM patients. Thus, compared with otherwise healthy adults, a
patient with HCM is 20 25 times more likely to exhibit a
QTc . 480 ms. Furthermore, 5% of these patients had a QTc
over the pro-arrhythmic threshold of 500 ms, generally considered
to represent a risk factor for potentially life-threatening arrhythmias irrespective of the associated condition. In most patients,
the QT prolongation appeared to reflect a more generally
severe phenotype in terms of LVH and presence of LVOT obstruction. In an important minority (9 of 62, 15%), however, a QTc .
480 ms was present despite mild HCM phenotype and no or
only mild symptoms, suggesting that abnormalities in cardiac repolarization may represent a primary feature of the disease in
selected cases, possibly subtended by specific gene defects.
The determinants of a specific individuals QTc are dependent
on numerous factors, including time of day and concurrent
illness or medications.15,25 In addition, if ones depolarization is
abnormal, for instance, in patients with left or right bundle
branch block, then the repolarization will assuredly be abnormal.26
The presence of an independent effect of both the JTc and QRS
intervals on QTc suggests that abnormal hypertrophied muscle
impacts both depolarization and repolarization in these patients.
The JTc correlates with a risk of cardiac events in patients with
coronary artery disease, even in the presence of abnormal QRS
duration measurements.21 In patients with HCM, the mechanism
of QT prolongation has been attributed previously to the sheer
mass of ventricular myocardium.16 18 In this study, we have
demonstrated that QT prolongation is associated with a higher
NYHA class at diagnosis, higher frequency of obstruction,
increased MLVWT, and higher rate of therapeutic septal reduction.
Also, QTc weakly correlated with the magnitude of left ventricular
outflow obstruction, suggesting that obstruction also influences
cardiac repolarization. These findings were consistent when examining either the QTc or the JTc interval.

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Although QT prolongation appeared to be generally driven by

severe phenotypic expressions of HCM, such as marked hypertrophy and presence of LVOT obstruction, we were able to identify a
small subset of patients in whom QT prolongation was present
despite a mild HCM phenotype, and appeared to represent a
primary, largely unexplained abnormality. Indeed, 9 of the 62 patients
with QTc . 480 ms had no evidence of LVOT obstruction and an
MLVWT ,20 mm. The average age in this subset was 51 + 20
years, three (33%) were males, and the mean MLVWT was 16.9 +
2.6 mm. The average QTc for these patients was 504 + 20 ms
(range 482 539 ms) with a QRS duration of 148 + 45 ms (range
88 202 ms) and a JTc duration of 345 + 56 ms (range 268
428 ms). Two patients had a family history of sudden death and
three patients underwent ICD placement. Only one of the three
patients had the ICD placed for secondary prevention, after having
documented sustained ventricular tachycardia. None of the three
patients has had an ICD shock in the available follow-up period.

J.N. Johnson et al.

1119

QT prolongation in patients with HCM

Table 2 Follow-up data for the 90 patients in the cohort who underwent implantable cardioverter defibrillator
placement
Total

QTc 480 ms

QTc > 480 ms

90
53/37

72
41/31

18
12/6

...............................................................................................................................................................................
n
Male/female
Follow-up (years)

4.9 + 3.3

5.0 + 3.4

4.4 + 3.0

Secondary prevention, n (%)

Mean no. of risk factors

15 (17)
1.8 + 1.0

12 (17)
1.8 + 0.9

3 (17)
1.9 + 1.1

34 (38)
24 (27)

29 (40)
17 (24)

Presence of RF, n (%)

NSVT on Holter
LVWT .30 mm

5 (28)
7 (39)

21 (23)

15 (21)

6 (33)

40 (44)
43 (48)

30 (42)
36 (50)

10 (56)
7 (39)

Appropriate discharges, n (%)

11 (12)

11 (15)

0 (0)

All values expressed as mean + SD. It must be noted that as not always feasible in clinical practice, not all risk factors were routinely assessed for each patient with Holter monitor
data least available for these patients. RF, risk factor; LVWT, left ventricular wall thickness; ABPR, abnormal blood pressure response.

Several authors have reported previously QT prolongation in

genotyped HCM patients.16 18 Jouven et al.16 examined 206
adult patients from 15 families. This included 112 unaffected
patients, 58 affected patients with LVH, and 36 affected patients
without LVH. All affected patients had mutations in either
MYBPC3-encoded myosin-binding protein C or the MYH7-encoded
beta-myosin heavy chain. The authors found a significant increase
in QT interval measurements in the affected patients, both with
and without LVH. Additionally, there were different patterns of
QT prolongation found between the two genotypes, where the
patients with beta-myosin heavy chain mutations had a prolonged
QTc even in the absence of hypertrophy.
In our large cohort of unrelated patients, no such genotypespecific differences in QTc were detected (Table 1). This may be
explained by our inclusion of only unrelated patients in the
study, in an attempt to prevent a single familial phenotype from
biasing the cohort at large. Uchiyama et al.18 recently published a
study of 154 HCM patients of whom 111 were genotype positive
and 43 were genotype negative. They found an increased QTc and
QT dispersion in patients with ECG abnormalities, both with and
without concurrent LVH. However, the only four patients in
the study to suffer sudden death over the follow-up period all
exhibited ECG abnormalities with LVH.18
Ultimately, in a small subset of patients who have had ICDs
placed, we did not find a significant difference in QRS, JTc,
or QTc between those who have received appropriate
VF-terminating therapies and those who thus far have not.
Further, a particular at risk patient subgroup was not delineated.
This certainly is limited by the relatively low event rate reported
in published HCM cohorts.3 Our results are consistent with a
study of 277 patients with HCM published in 2001, which did
not find QT dispersion or QTc predictive of a sudden death
risk.27 The risk associated with QT prolongation in HCM
appears to be markedly different from that of patients with
LQTS. This is likely due to the expected multi-factorial origin
of QT prolongation in HCM (hypertrophy, myocyte disarray,

obstruction), as opposed to a specific electrical origin in

LQTS, which may confer a higher arrhythmogenic potential
intrinsically.
However, considering the small sample size and low event rate
expected in HCM cohorts, and knowing that a QTc . 500 ms is a
risk factor in multiple disease entities,9 14 it would be premature
to dismiss QT prolongation in a patient with HCM as an innocuous
finding. Specifically, the concomitant use of medications with
known QT prolonging potential, such as the frequently employed
amiodarone or sotalol, in HCM patients with baseline prolongation
of the QTc may have potentially adverse consequences, by
further enhancing pro-arrhythmic pre-disposition and precipitating
torsades de pointes.
Our findings have important clinical implications. Routine QTc
assessment should be performed in patients with HCM, particularly in those for whom the concomitant use of medications
with a known QT-prolonging effect is intended. The use of
QT-prolonging drugs should be weighed against potential risks,
and the QT interval monitored regularly during treatment. Furthermore, these patients should be adequately counselled with
regard to potential interaction with other QT-prolonging drugs
(antibiotics, etc.) and of common electrolyte disturbances. Of
note, in this study, a QTc cut-off value of 480 ms identified a
subset of patients with clearly abnormal duration of repolarization
for this specific disease. Therefore, we would propose that this
value be used in clinical practice as the threshold prompting
careful consideration regarding the concomitant use of medications with QT-prolonging potential. The role of QT prolongation in HCM requires further investigation with regard to a
potential impact on prognosis.

Limitations
This study is limited by the low event rate as expected in most
HCM cohorts. Holter recordings were not universally assessed
for non-sustained ventricular tachycardia (NSVT) in the present
cohort; although it might have been interesting to evaluate the

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ABPR on exercise
(Near)syncope
Family Hx of sudden death

1120
relationship of this feature with QTc, it is well known that arrhythmias recorded during Holter monitoring (including primary NSVT)
have poor positive predictive accuracy with regard to events in
HCM. Therefore, such analysis would not have added decisive
information regarding the prognostic relevance of QTc prolongation in our patients. Furthermore, in Figure 1, we compared
our HCM cohort with a published historical control group,23,24
which was, therefore, not a patient-level comparison. Accordingly,
there are inherent limitations to using a historical comparison
group, including possible differences in the methodology used
which cannot be established.

Conclusions

Acknowledgements

7.

8.

9.

10.

11.

12.

13.

14.

The investigators express their gratitude to patients who have

sought clinical evaluation at their respective medical centres.

15.

Funding

16.

This work was supported by the following sources: M.J.A. research

programme was supported by the Mayo Clinic Windland Smith Rice
Comprehensive Sudden Cardiac Death Program. M.J.A. is also an
Established Investigator of the American Heart Association and is supported by the National Institutes of Health (HD42569 and HL094291).
F.C. and I.O. are supported by Ministero Istruzione Universita` e
Ricerca (PRIN) and the European Union (STREP Project 241577
BIG HEART, 7th European Framework Program).

17.
18.

19.

Conflict of interest: M.J.A. is a consultant for Biotronik, Boston

Scientific Corporation, Medtronic, PGxHealth, and St. Jude Medical Inc.

20.

References

21.

1. Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA 2002;287:

1308 1320.
2. Bos JM, Towbin JA, Ackerman MJ. Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy. J Am Coll Cardiol 2009;
54:201211.
3. Maron BJ, Spirito P, Shen WK, Haas TS, Formisano F, Link MS, Epstein AE,
Almquist AK, Daubert JP, Lawrenz T, Boriani G, Estes NA 3rd, Favale S,
Piccininno M, Winters SL, Santini M, Betocchi S, Arribas F, Sherrid MV, Buja G,
Semsarian C, Bruzzi P. Implantable cardioverter-defibrillators and prevention of
sudden cardiac death in hypertrophic cardiomyopathy. JAMA 2007;298:405 412.
4. McKenna WJ, Goodwin JF. The natural history of hypertrophic cardiomyopathy.
Curr Probl Cardiol 1981;6:1 26.
5. Spirito P, Autore C, Rapezzi C, Bernabo P, Badagliacca R, Maron MS,
Bongioanni S, Coccolo F, Estes NA, Barilla CS, Biagini E, Quarta G, Conte MR,
Bruzzi P, Maron BJ. Syncope and risk of sudden death in hypertrophic cardiomyopathy. Circulation 2009;119:1703 1710.
6. Kofflard MJ, Ten Cate FJ, van der Lee C, van Domburg RT. Hypertrophic cardiomyopathy in a large community-based population: clinical outcome and

22.
23.

24.
25.
26.
27.

identification of risk factors for sudden cardiac death and clinical deterioration.
J Am Coll Cardiol 2003;41:987 993.
Cecchi F, Maron BJ, Epstein SE. Long-term outcome of patients with hypertrophic
cardiomyopathy successfully resuscitated after cardiac arrest. J Am Coll Cardiol
1989;13:1283 1288.
McKenna W, Deanfield J, Faruqui A, England D, Oakley C, Goodwin J. Prognosis
in hypertrophic cardiomyopathy: role of age and clinical, electrocardiographic and
hemodynamic features. Am J Cardiol 1981;47:532 538.
Goldenberg I, Moss AJ, Peterson DR, McNitt S, Zareba W, Andrews ML,
Robinson JL, Locati EH, Ackerman MJ, Benhorin J, Kaufman ES, Napolitano C,
Priori SG, Qi M, Schwartz PJ, Towbin JA, Vincent GM, Zhang L. Risk factors
for aborted cardiac arrest and sudden cardiac death in children with the congenital long-QT syndrome. Circulation 2008;117:2184 2191.
Goldenberg I, Moss AJ, Bradley J, Polonsky S, Peterson DR, McNitt S, Zareba W,
Andrews ML, Robinson JL, Ackerman MJ, Benhorin J, Kaufman ES, Locati EH,
Napolitano C, Priori SG, Qi M, Schwartz PJ, Towbin JA, Vincent GM, Zhang L.
Long-QT syndrome after age 40. Circulation 2008;117:2192 2201.
Hobbs JB, Peterson DR, Moss AJ, McNitt S, Zareba W, Goldenberg I, Qi M,
Robinson JL, Sauer AJ, Ackerman MJ, Benhorin J, Kaufman ES, Locati EH,
Napolitano C, Priori SG, Towbin JA, Vincent GM, Zhang L. Risk of aborted
cardiac arrest or sudden cardiac death during adolescence in the long-QT
syndrome. JAMA 2006;296:1249 1254.
Sauer AJ, Moss AJ, McNitt S, Peterson DR, Zareba W, Robinson JL, Qi M,
Goldenberg I, Hobbs JB, Ackerman MJ, Benhorin J, Hall WJ, Kaufman ES,
Locati EH, Napolitano C, Priori SG, Schwartz PJ, Towbin JA, Vincent GM,
Zhang L. Long QT syndrome in adults. J Am Coll Cardiol 2007;49:329 337.
Seth R, Moss AJ, McNitt S, Zareba W, Andrews ML, Qi M, Robinson JL,
Goldenberg I, Ackerman MJ, Benhorin J, Kaufman ES, Locati EH, Napolitano C,
Priori SG, Schwartz PJ, Towbin JA, Vincent GM, Zhang L. Long QT syndrome
and pregnancy. J Am Coll Cardiol 2007;49:1092 1098.
Chugh SS, Reinier K, Singh T, Uy-Evanado A, Socoteanu C, Peters D, Mariani R,
Gunson K, Jui J. Determinants of prolonged QT interval and their contribution to
sudden death risk in coronary artery disease: the Oregon Sudden Unexpected
Death Study. Circulation 2009;119:663 670.
Kenigsberg DN, Khanal S, Kowalski M, Krishnan SC. Prolongation of the QTc
interval is seen uniformly during early transmural ischemia. J Am Coll Cardiol
2007;49:1299 1305.
Jouven X, Hagege A, Charron P, Carrier L, Dubourg O, Langlard JM, Aliaga S,
Bouhour JB, Schwartz K, Desnos M, Komajda M. Relation between QT duration
and maximal wall thickness in familial hypertrophic cardiomyopathy. Heart 2002;
88:153 157.
Martin AB, Garson A Jr., Perry JC. Prolonged QT interval in hypertrophic and
dilated cardiomyopathy in children. Am Heart J 1994;127:64 70.
Uchiyama K, Hayashi K, Fujino N, Konno T, Sakamoto Y, Sakata K, Kawashiri MA,
Ino H, Yamagishi M. Impact of QT variables on clinical outcome of genotyped
hypertrophic cardiomyopathy. Ann Noninvasive Electrocardiol 2009;14:65 71.
Olivotto I, Girolami F, Ackerman MJ, Nistri S, Bos JM, Zachara E, Ommen SR,
Theis JL, Vaubel RA, Re F, Armentano C, Poggesi C, Torricelli F, Cecchi F. Myofilament protein gene mutation screening and outcome of patients with hypertrophic
cardiomyopathy. Mayo Clin Proc 2008;83:630 638.
Van Driest SL, Vasile VC, Ommen SR, Will ML, Tajik AJ, Gersh BJ, Ackerman MJ.
Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy. J Am Coll Cardiol 2004;44:1903 1910.
Crow RS, Hannan PJ, Folsom AR. Prognostic significance of corrected QT and
corrected JT interval for incident coronary heart disease in a general population
sample stratified by presence or absence of wide QRS complex: the ARIC Study
with 13 years of follow-up. Circulation 2003;108:1985 1989.
Bazett H. An analysis of the time-relations of electrocardiograms. Heart 1920;7:
353 370.
Mason JW, Ramseth DJ, Chanter DO, Moon TE, Goodman DB, Mendzelevski B.
Electrocardiographic reference ranges derived from 79,743 ambulatory subjects.
J Electrocardiol 2007;40:228 234.
Taggart NW, Haglund CM, Tester DJ, Ackerman MJ. Diagnostic miscues in congenital long-QT syndrome. Circulation 2007;115:2613 2620.
Johnson JN, Ackerman MJ. QTc: how long is too long? Br J Sports Med 2009;43:
657 662.
Talbot S. QT interval in right and left bundle-branch block. Br Heart J 1973;35:
288 291.
Maron BJ, Leyhe MJ 3rd, Casey SA, Gohman TE, Lawler CM, Crow RS, Maron MS,
Hodges M. Assessment of QT dispersion as a prognostic marker for sudden death
in a regional nonreferred hypertrophic cardiomyopathy cohort. Am J Cardiol 2001;
87:114 115, A9.

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Compared with ,1 in 200 otherwise healthy adults, QT prolongation (QTc . 480 ms) was present in 1 out of 8 patients
with HCM. The QTc was partly reflective of the degree of
cardiac hypertrophy and LVOT obstruction. Because of its
pro-arrhythmic potential and its potential relevance to management and risk stratification, routine QTc assessment should be
performed in patients with HCM, particularly when concomitant
use of QT-prolonging medications is considered.

J.N. Johnson et al.