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153
CARDIOVASCULAR MEDICINE
Relation between QT duration and maximal wall
thickness in familial hypertrophic cardiomyopathy
X Jouven, A Hagege, P Charron, L Carrier, O Dubourg, J M Langlard, S Aliaga,
J B Bouhour, K Schwartz, M Desnos, M Komajda
.............................................................................................................................
Heart 2002;88:153–157
See end of article for
authors’ affiliations
.......................
Correspondence to:
Dr Xavier Jouven, Service
de Cardiologie, Hôpital
Européen Georges
Pompidou, 20 rue Leblanc,
75015 Paris, France;
xavier.jouven@
hop.egp.ap-hop-paris.fr
Accepted 17 April 2002
.......................
Background: QT abnormalities have been reported in left ventricular hypertrophy and hypertrophic
cardiomyopathy.
Objective: To determine the relation between left ventricular hypertrophy and increased QT interval in
familial hypertrophic cardiomyopathy.
Methods: The QT interval was measured in 206 genotyped adult subjects with familial hypertrophic
cardiomyopathy from 15 unrelated families carrying mutations in the β myosin heavy chain (β-MHC)
gene (five families, n = 68) or the cardiac myosin binding protein C (MyBPC) gene (10 families,
n = 138). Subjects were classified as genetically unaffected (controls, n = 112), affected with left ventricular hypertrophy (penetrants, n = 58), or affected without left ventricular hypertrophy
(non-penetrants, n = 36).
Results: There was a significant increase in QTmax and QTmin from controls to non-penetrants and
penetrants for both the MyBPC group (p < 0.001 and p < 0.001, respectively) and the β-MHC group
(p < 0.001 and p < 0.001, respectively). In the MyBPC group, the increase in the QT interval could
be explained by increased left ventricular hypertrophy. In the β-MHC group, non-penetrants had a significantly longer QTmax than controls despite the absence of left ventricular hypertrophy, and a similar
QT interval to penetrants despite a lesser degree of left ventricular hypertrophy.
Conclusions: In familial hypertrophic cardiomyopathy, genetically affected subjects without left
ventricular hypertrophy may have a prolonged QT duration, which depends not only on the degree of
left ventricular hypertrophy, when present, but also on the causative mutation.
H
ypertrophic cardiomyopathy is associated with an
increased risk of ventricular tachyarrhythmias and sudden death.1–6 A prolonged QT interval and increased QT
dispersion (QTd) have been observed in affected
individuals7–13 and may contribute to the occurrence of
ventricular arrhythmias. However, the relations between left
ventricular hypertrophy, increased QT interval, and QTd are
unclear.8 11 13 In hypertrophic cardiomyopathy, it is not known
whether these abnormalities only reflect the increased
myocardial thickness, or whether they are a result of the
genetic mutation. If the latter were true, it might explain the
occurrence of sudden death among genetically affected
subjects without left ventricular hypertrophy.14 15
Molecular genetic studies in individuals with familial
hypertrophic cardiomyopathy16 17 can discriminate between
those not genetically affected, those who are affected and have
ECG or echocardiographic abnormalities (penetrants), and
those who are affected but do not have ECG or echocardiographic abnormalities (non-penetrants). The QT interval and
QT dispersion have not been characterised in genotyped cases
of familial hypertrophic cardiomyopathy. Furthermore, we
know nothing about the behaviour of QT in non-penetrants.
Our aim in this study was therefore to assess the QT interval
and QT dispersion in a large genotyped cohort of adult cases of
familial hypertrophic cardiomyopathy.
METHODS
Population
Persons with known causative mutations from among
genotyped families with hypertrophic cardiomyopathy16 17
were included in the study. Informed consent was obtained in
accordance with a study protocol approved by the ethics committee of the Centre Hospitalier Universitaire de la PitiéSalpetrière.
The subjects had an ECG and a physical and Doppler
echocardiographic examination, and provided blood samples
for laboratory tests. Those with a clinical cause for left
ventricular hypertrophy, such as valvar heart disease or high
blood pressure, and anyone being treated with amiodarone or
sotalol were excluded from the analyses. Because of age
related changes in myocardial thickness in children, subjects
under the age of 18 were excluded.
QT measurements
A standard 12 lead ECG was recorded in all subject at 25 mm/s
paper speed with a 10 mm/mV gain. Measurements of ECG
intervals were performed manually, using a standardised
approach. The QT interval was measured from the onset of the
QRS complex to the end of the T wave at the level of the isoelectric baseline. In the presence of a U wave, the end of the T
wave was assessed using the most similar pattern of the 16
possible combinations of T and U waves schematised by Lepeschkin and Surawicz.18 When the end of the T wave could not
be determined reliably or when the T wave was of very low
amplitude (< 1 mm), the lead was excluded from the
analysis. An average of three consecutive cycles for each lead
was obtained. The QT interval was corrected for heart rate
using Hodges’s linear correction19:
QTc = QT + 1.75(heart rate − 60)
QTd was defined as the difference between maximum
(QTcmax) and minimum (QTcmin) values of the QT intervals
.............................................................
Abbreviations: β-MHC, β-myosin heavy chain; MyBPC, cardiac myosin
binding protein C; QTc, corrected QT; QTd, QT dispersion
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154
in any of the 12 leads in which it was measured. Because of the
linearity, rate correction is unnecessary (that is, with Hodge’s
formula, QTd calculated from corrected QT intervals is identical to QTd calculated from uncorrected intervals). All
measurements were performed by the same investigator using
this standardised approach, blinded to the clinical, genetic,
and echocardiographic diagnosis. Subjects with atrial fibrillation or complete bundle branch block, or in whom QT interval
measurement was only possible in fewer than eight leads,
were excluded from analysis.
Reproducibility assessment
Thirty ECGs were randomly reanalysed to assess the intraobserver reproducibility of QT interval measurements. The
largest mean intraobserver QT error was noticed in lead III
(2.2%) and the lowest in lead V3 (1%). The ranges and means
(SD) of the intraobserver error, with paired t tests, were
respectively:
for Qtmax: 0–30 ms; 2 (8) ms (NS)
for Qtmin: 0–30 ms; −4 (14) ms (NS)
for QTd: 0–50 ms, 10 (18) ms (p = 0.01)
Genetic analysis
Genotypic assessments were obtained from family members using amplification, polymerase chain reaction, microsatellite typing, and sequencing techniques as previously
described.20 21 Fifteen families with 12 different mutations
were studied: five families were associated with four
mutations in the β-myosin heavy chain (β-MHC) gene
(Arg403Leu, Arg719Trp, Arg723Cys, Glu483Lys), and 10 families were
associated with eight mutations in the cardiac myosin binding
protein C gene (DelExon25, SASint7, SASint20, Glu542Gln,
SASint23, SASint11, BPint23, DelExon33).
Echocardiographic analysis
Cross sectional echocardiographic examinations were performed in three separate institutions with standard echocardiographic systems. Ultrasonic images were obtained in cross
sectional planes using standard transducer positions, and
stored on VHS videotape for subsequent analysis. All echocardiographic measurements were performed in a core laboratory
by three senior echocardiographists who read the recording
blindly and without knowledge of the genetic diagnosis. M
mode measurements of end diastolic left ventricular wall
thickness were made at the onset of the QRS complex, according to the recommendations of the American Society of Echocardiography. In cases of disagreement, analyses were
reviewed by the three readers and definitive agreement
achieved.
Penetrance of the disease
The penetrance of the disease was determined as previously
described.17 In brief, the criteria used (in the absence of any
cause of left ventricular hypertrophy) were as follows:
(1) a maximum left ventricular end diastolic wall thickness
> 13 mm
(2) the presence of major abnormalities on the ECG—that is,
left ventricular hypertrophy assessed by a Romhilt–Estes score
of > 4,22 Q waves of > 0.04 s or more than one third of the
width of the R wave, or significant ST–T segment changes
(3) a combination of (1) and (2).
Statistical analysis
Values are expressed as mean (SD). As individuals within a
family were not independent, conventional statistical procedures could not be used. Statistical analyses were carried out
using the estimating equations technique proposed by Liang
and Zeger.23 SAS procedures (Statistical Analysis System, Cary,
North Carolina, USA) were used for analysis. Within both the
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Jouven, Hagege, Charron, et al
β-MHC group and the MyBPC group, characteristics of
controls, non-penetrants, and penetrants were compared
using variance analysis and global tests for linear trend when
indicated (GENMOD procedures, with a probability value of
p < 0.01 considered as significant). Correlations were assessed using Spearman’s comparison of ranks.
RESULTS
Study group
Among the 273 genotyped subjects, 67 were excluded from the
analysis. Causes of exclusion were the following: age < 18
years (n = 40); another cause of left ventricular hypertrophy
(n = 3); atrial fibrillation (n = 3); complete bundle branch
block (n = 10); amiodarone or sotalol treatment (n = 5); and
QT intervals measurements in fewer than eight of the 12 leads
(n = 6).
The remaining 206 adults, coming from 15 unrelated families, completed clinical, ECG, biological, genetic, and echocardiographic examinations. There were 112 men and 94 women,
with a mean (SD) age of 39.4 (15.8) years (range 18–91 years).
Ninety four subjects were genetically affected, including 58
penetrants and 36 non-penetrants. Overall, 138 subjects came
from 10 families carrying mutations in the MyBPC gene
encoding for the sarcomeric protein C (79 controls, 24
non-penetrants, and 35 penetrants), and 68 subjects came
from five families carrying mutations in the β-MHC gene
encoding for the β-myosin heavy chain (33 controls, 12
non-penetrants, and 23 penetrants).
No significant difference was observed between the 10
families with mutations in the MyBPC gene, or between the
five families with mutations in the β-MHC gene. The families
were therefore pooled into two groups (MyBPC group and
β-MHC group). The characteristics of controls, nonpenetrants, and penetrants are compared in table 1. In neither
group were the sex ratio, body mass index, heart rate, or
systolic and diastolic blood pressure significantly different
between controls, non-penetrants, or penetrants. In the
MyBPC group only, penetrant subjects were significantly older
than non-penetrant subjects and controls.
In the MyBPC and β-MHC groups, there was a significant
trend towards a linear increase in maximum wall thickness
(p < 0.001 and p < 0.001, respectively), left atrial diameter
(p < 0.001 and p < 0.01), and myocardial mass index
(p < 0.001 and p < 0.001) from controls, through nonpenetrant subjects, to penetrant subjects.
The maximum wall thickness was greater in penetrants
with a mutation in the β-MHC gene than in those with a
mutation in the MyBPC gene (20.9 (4.8) mm v 17.6 (4.6) mm,
p < 0.001), while it was comparable in the non-penetrants
(9.8 (1.8) mm v 10.4 (1.7) mm, NS) and the controls (10.2
(2.2) mm v 9.2 (1.6) mm, NS).
Among penetrant subjects, the following variables were not
statistically different between the MyBPC and the β-MHC
groups: left ventricular outflow tract gradient > 30 mm Hg
(11.6% v 4.3%, NS); mitral valve systolic anterior motion
(25.7% v 39.1%, NS); and abnormal T waves (57.1% v 43.5%,
NS).
QT analysis
There was a linear trend in all 12 leads towards an increase in
QTc interval (p < 0.01), QTcmax (p < 0.0001), and QTcmin
(p < 0.0001), but only a non-significant trend in QTd
(p < 0.02) from controls, through non-penetrant subjects, to
penetrant subjects in the MyBPC group. In this group, QTcmax
and QTcmin values in the penetrants remained significantly
different from the values in the non-penetrants (p < 0.0003
and p < 0.01, respectively), while there was no difference
between non-penetrants and controls (p < 0.03 and NS,
respectively) (fig 1).
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QT duration and wall thickness in hypertrophic cardiomyopathy
155
Table 1 Clinical and echocardiographic data on controls, non-penetrants, and penetrants from families carrying
mutations in the cardiac myosin binding protein C or β myosin heavy chain genes
β-MHC
MyBPC
Male/female
Age (years)
Heart rate (beats/min)
BMI (kg/m2)
Systolic BP (mm Hg)
MWT (mm)
LA diameter (mm)
LVMI (g/m2)
Controls
(n=79)
Non-penetrants
(n=24)
Penetrants
(n=35)
p Value*
Controls
(n=33)
Non-penetrants
(n=12)
Penetrants
(n=23)
p Value*
37/42
37 (14)
68 (10)
23.5 (3.6)
124 (11)
9.2 (1.6)
33 (6)
37.8 (7.0)
10/14
38 (19)
65 (12)
23.8 (3.1)
126 (12)
10.4 (1.7)
35 (4)
40.6 (8.0)
23/12
45 (15)
66 (17)
24.7 (2.8)
124 (11)
17.6 (4.6)
41 (9)
57.9 (12.4)
NS
0.02
NS
NS
NS
0.0001
0.0001
0.0001
19/14
39 (14)
73 (17)
22.8 (3.1)
128 (9)
10.2 (2.2)
34 (5)
36.6 (8.5)
6/6
34 (12)
69 (17)
21.6 (2.8)
119 (8)
9.8 (1.8)
35 (4)
37.4 (10.0)
14/9
42 (15)
65 (12)
23.7 (3.4)
132 (21)
20.9 (4.8)
40 (9)
63.7 (12.5)
NS
NS
NS
NS
NS
0.0001
0.03
0.0001
Values are n or mean (SD).
*p Values for global variance analysis.
β-MHC, β-myosin heavy chain gene; BMI, body mass index; BP, blood pressure; LA, left atrial; LVMI, left ventricular mass index; MyBPC, cardiac myosin
binding protein C gene; non-penetrant, genetically affected but no left ventricular hypertrophy; penetrant, genetically affected with left ventricular
hypertrophy.
Similarly in the β-MHC group, there was a trend for a linear
increase in QTc interval in all leads (p < 0.01) excepted L1
(p < 0.03) and L2 (p < 0.02), in QTcmax (p < 0.0001), and in
QTcmin (p < 0.0001), but not QTd, from controls, through
non-penetrant subjects, to penetrant subjects. In all leads, the
QTc intervals of non-penetrants were similar to the values in
penetrants. Finally, the differences in QTcmax and QTcmin
between penetrant and non-penetrant subjects were not
significant, while the difference between non-penetrants and
controls remained significant (p < 0.01 and p < 0.01, respectively).
In penetrant subjects, Qtcmax was longer in patients with a
mutation on the MyBPC gene than in those with a mutation
on the β-MHC gene (450 (32) ms v 435 (22) ms, p < 0.01), but
there was no significant difference in the prevalence of
complete bundle branch block and electrical left ventricular
Figure 1 QTcmax, QTcmin, QTd, and maximum wall thickness in controls, non-penetrant subjects, and penetrant subjects in subjects
originating from families with mutations in the MyBPC or β-MHC genes; p value for 2×2 tests. β-MHC, β-myosin heavy chain; C, control; MWT,
maximum wall thickness; MyBPC, cardiac myosin binding protein C; NP, non-penetrant: genetically affected but no left ventricular hypertrophy;
P, penetrant: genetically affected with left ventricular hypertrophy; QTc, corrected QT interval; QTd, QT dispersion.
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156
Jouven, Hagege, Charron, et al
Figure 2 Correlations between
QTcmax and maximum wall thickness
in subjects with mutations in the
MyBPC or β-MHC genes; p value for
Spearman rank correlations. β-MHC,
β-myosin heavy chain; MWT,
maximum wall thickness; MyBPC,
cardiac myosin binding protein C;
QTc, corrected QT interval.
hypertrophy between the two groups. In non-penetrants and
controls, Qtcmax was not significantly different between the
two groups.
The positive correlation (fig 2) of maximum wall thickness
with QTcmax and QTcmin in genetically affected subjects
(non-penetrants and penetrants) was significant in the
MyBPC group (r = 0.41, p = 0.002; and r = 0.29, p = 0.01,
respectively) but not in the β-MHC group (r = 0.22, NS; and
r = 0.08, NS).
DISCUSSION
end diastolic wall thickness of more than 13 mm and/or the
presence of major abnormalities on the ECG (left ventricular
hypertrophy, Q waves, and significant ST–T segment changes).
On the other hand, in view of the prolonged QT interval, it is
questionable whether such individuals should be classed as
truly non-penetrant. The prolonged QT interval may increase
the risk of ventricular arrhythmias and could explain the
occurrence of sudden death in patients with hypertrophic cardiomyopathy in the absence of left ventricular hypertrophy, as
reported previously.14 15
QT duration and myocardial hypertrophy
In penetrant subjects, and despite a smaller maximum wall
thickness, patients with a mutation on the MyBPC gene had a
longer Qtcmax than those with a mutation on the β-MHC
gene. Mutations in the MyBPC or β-MHC genes showed
different patterns with respect to the QT interval.
In the MyBPC group there was a similar pattern of increase
in maximum wall thickness, QTcmax, and QTcmin between
controls, non-penetrants, and penetrants, and the correlation
between QTcmax (or QTcmin) and maximum wall thickness
was significant. These findings suggest that the increased QT
interval observed in individuals with mutations in the MyBPC
gene is related to myocardial hypertrophy. On the other hand,
in subjects with a mutation in the β-MHC gene, nonpenetrants had significant prolongation of QTcmax and
Qtcmin, despite the absence of left ventricular hypertrophy in
this group. The non-penetrants had similar QTcmax and QTcmin values to the penetrants, despite pronounced differences
in maximum wall thickness. Thus in mutations of the β-MHC
gene, a prolonged QT interval does not appear to be related
solely to myocardial hypertrophy.
Possible mechanisms
Mechanisms other than myocardial hypertrophy could be
involved in QT prolongation. Hyperreactivity of the adrenergic
system and an imbalance in sympathetic/parasympathetic
tone have been described in patients with hypertrophic
cardiomyopathy.24 25 Slight differences in sympathetic tone,
which affect the RR interval to a minor degree, have been
shown to cause much greater differences in QT intervals in
patients with hypertrophic cardiomyopathy compared with
controls.25 Thus the response of the ventricular myocardium to
changes in sympathetic tone may be increased in patients
with hypertrophic cardiomyopathy.
Regional myocardial fibrosis, scarring, or ischaemia have
also been described in patients with hypertrophic cardiomyopathy. In a recent study, Yoshida found perfusion abnormalities in 69% of such patients.26
A direct or indirect effect of the gene mutation on QT
abnormalities cannot be excluded.27 Familial long QT syndrome is a disorder characterised by abnormal ventricular
repolarisation, ventricular arrhythmias triggered by sympathetic nervous activation, and sudden death.28 In long QT syndrome it has been possible to trace specific mutations on ion
channel genes, and numerous novel mutations have been
described.29 Thus in hypertrophic cardiomyopathy, mutations
in the genes encoding for sarcomere proteins may interfere
with genes encoding for channel subunits, and this could
increase the QT interval independently of any myocardial
hypertrophy. This hypothesis would conveniently explain the
behaviour of the QT interval in individuals with the β-MHC
gene mutation.
QT abnormalities in non-penetrant subjects
QTcmax and QTcmin were significantly longer in nonpenetrants carrying a mutation in the β-MHC gene than in
controls. These subjects did not have the usual criteria of penetrance of the disease—that is, a maximum left ventricular
Limitations
Our findings were obtained in a selected population, and thus
the conclusions are limited to families with mutations in the
β-MHC and MyBPC genes. Moreover, because of the small differences between controls, non-penetrant subjects, and
Up to now, QT abnormalities in patients with hypertrophic
cardiomyopathy have only been described in non-genotyped
populations. Published reports have concerned only case–
control studies involving various different control populations
(healthy volunteers or patients, stratified or not for age and
sex), and various types of case (usually a combination of cases
of sporadic and familial hypertrophic cardiomyopathy).7–13
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QT duration and wall thickness in hypertrophic cardiomyopathy
penetrant subjects, the QT abnormalities cannot be used at the
individual level for diagnosing hypertrophic cardiomyopathy
within a family.
No significant differences were observed between separate
families with mutations within a given gene, but the power to
detect such differences was low. Combining families into
groups according to gene type (β-MHC or MyBPC) may have
pooled individuals with very different forms of expression of
the disease. However, in the absence of preliminary data, this
approach appeared to be the most logical.
When subjects treated with β blocking agents (n = 9) were
excluded from the analysis, the results did not change significantly. Furthermore, as only penetrant subjects were treated
with β blockers, this variable did not affect the differences in
QT interval observed between the controls and the nonpenetrant subjects.
Different methods have been described to measure the QT
interval, and there is at present no gold standard. Manual
measurements7–9 12 were used in the present study, with the
usual limitations of that method—it is time consuming, there
is high interobserver variability, and there is poor
reproducibility.30 31 By using a single trained cardiologist with
a standardised measurement, we eliminated interobserver
variability and we increased the reproducibility, which was
higher than previously reported.30 31 On the other hand, automatic measurements10 11 are faster and provide better reproducibility, though their reliability is still questioned, particularly in abnormal hearts.32 Finally, in a study to validate an
automated method in patients with hypertrophic cardiomyopathy, Savelieva and colleagues showed that both manual
and automatic methods were suitable, but that they characterised different facets of the shape of the T wave.33 Manual
measurements may reduce the differences in QT interval
observed between controls, non-penetrants, and penetrants.
The absence of significant differences in QTd between these
three groups in our study could reflect both the unreliability of
the measurements and a large overlap with the healthy population.
Conclusions
In familial hypertrophic cardiomyopathy associated with
mutation of the β-MHC gene, the prolonged QT interval
appears to be partially independent of myocardial hypertrophy. Further studies on other gene mutations will be useful in
determining whether the QT abnormalities in this condition
are related to prognosis.
.....................
Authors’ affiliations
X Jouven, A Hagege, S Aliaga, M Desnos, Service de Cardiologie,
Hôpital Européen Georges Pompidou, Paris, France
P Charron, M Komajda, Service de Cardiologie, Hôpital
Pitié-Salpêtrière, Paris, France
L Carrier, K Schwartz, INSERM Unit 153, Paris, France
O Dubourg, Service de Cardiologie, Hôpital Ambroise Paré, Nantes,
France
J M Langlard, J B Bouhour, Service de Cardiologie, Hôpital Laennec,
Nantes, France
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Relation between QT duration and maximal wall
thickness in familial hypertrophic
cardiomyopathy
X Jouven, A Hagege, P Charron, L Carrier, O Dubourg, J M Langlard, S
Aliaga, J B Bouhour, K Schwartz, M Desnos and M Komajda
Heart 2002 88: 153-157
doi: 10.1136/heart.88.2.153
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