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Although gender may be one of the important factors modifying phenotypic expression in hypertrophic cardiomyopathy (HCM), there has been little information on it.
Methods and results
We investigated gender differences in the clinical features of HCM caused by cardiac myosin-binding protein C gene (MYBPC3) mutations. Sixty-one subjects (28 families) carrying MYBPC3 mutations were studied. Of the 61 subjects with MYBPC3 mutations, 50 patients including 23 female patients were phenotype-positive by echocardiography. Disease penetrance in subjects aged ≤40 years old was 92% in males and 67% in females. Females showed delayed onset of left ventricular hypertrophy compared with males in subjects who were genotype-positive. Female patients were more symptomatic at diagnosis than were males (mean New York Heart Association class: 1.7 ± 0.8 versus 1.2 ± 0.4, p = 0.012). From a longitudinal point of view by age, no significant gender difference in cardiovascular deaths or cardiovascular events was found. During the follow-up period after diagnosis of HCM (13 ± 8 years), female patients who were phenotype-positive had significantly more frequent heart failure events than did phenotypically affected male patients (p = 0.028).
Conclusions
Although females with MYBPC3 mutations showed later onset of the disease, female patients were more symptomatic at diagnosis and had more frequent heart failure events once they had developed hypertrophy.
Hypertrophic cardiomyopathy (HCM) is a primary and genetically transmitted myocardial disorder characterized by thickening of the left ventricular (LV) wall in the absence of another cardiac or systemic disease capable of producing the magnitude of evident hypertrophy [
American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines.
A systematic review and meta-analysis of genotype–phenotype associations in patients with hypertrophic cardiomyopathy caused by sarcomeric protein mutations.
]. HCM is usually caused by sarcomere protein gene mutations, and the cardiac phenotype has great diversity in morphologic features, age of onset, and clinical course [
American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines.
A systematic review and meta-analysis of genotype–phenotype associations in patients with hypertrophic cardiomyopathy caused by sarcomeric protein mutations.
]. This phenotypic heterogeneity suggests the existence of some factors that modify the disease presentation. Gender is thought to be one of the important modifying factors in HCM because female patients with HCM had been reported to be older and more symptomatic than male patients at the time of their initial diagnosis [
Gender-specific differences in the clinical features of hypertrophic cardiomyopathy in a community-based Japanese population: results from Kochi RYOMA study.
]. These gender-specific differences can be explained by social, endocrine, or genetic factors. However, there has been little information on gender differences in HCM patients carrying sarcomere protein gene mutations [
]. In this study, we investigated the gender differences in clinical features of familial HCM caused by cardiac myosin-binding protein C gene (MYBPC3) mutations.
Methods
Subjects
We studied 28 HCM families with disease-causing MYBPC3 mutations at Kochi Medical School Hospital. The diagnosis of HCM was based on echocardiographic demonstration of unexplained left ventricular hypertrophy (LVH), i.e. maximum LV wall thickness ≥15 mm. Relatives of the proband patients were contacted by the probands themselves and visited our clinic of their own free will. Following the identification of mutations, pedigree analysis including both clinical evaluation and genotyping was performed. Informed consent was obtained from all subjects or their parents in accordance with the guidelines of the Ethics Committee on Medical Research of Kochi Medical School.
Clinical evaluation
Evaluation of patients included medical history, clinical examination, 12-lead electrocardiography (ECG), and conventional and Doppler echocardiography. The diagnosis of phenotype-positive, that is clinical diagnosis of HCM, was based on echocardiographic demonstration of unexpected LVH (maximum LV wall thickness ≥15 mm). LV end-diastolic diameter (LVEDD) and end-systolic diameter (LVESD) were measured from M-mode and 2D images obtained from parasternal long-axis views, and fractional shortening [%FS = (LVEDD − LVESD)/LVEDD × 100] was calculated. Global ejection fraction (EF) was estimated from apical two- and four-chamber views using modified Simpson's method. Left ventricular outflow tract obstruction (LVOTO) was defined by the presence of a basal peak subaortic gradient ≥30 mmHg calculated from continuous-wave Doppler using the simplified Bernoulli equation. Dilated phase of HCM was defined as LV systolic dysfunction of global EF < 50%. Concomitant coronary artery disease was excluded by coronary angiography and/or myocardial scintigraphy.
For survival analysis, three modes of HCM-related death were defined: (1) sudden and unexpected death, in which collapse occurred in the absence of or <1 h from the onset of symptoms in patients who previously experienced a relatively stable or uneventful clinical course; (2) heart failure-related death, which was in the context of progressive cardiac decompensation ≥1 year before death, particularly if complicated by pulmonary edema or evolution to the end-stage phase; and (3) stroke-related death, which occurred as a result of probable or proven embolic stroke. Other morbid events included (1) hospitalization for heart failure, (2) embolic stroke admission, (3) spontaneous sustained ventricular tachycardia associated with hemodynamic instability or appropriate implantable cardioverter defibrillator discharge, and (4) progression to New York Heart Association (NYHA) functional class III or IV status, which required additional treatment. Data on survival and clinical status of patients were obtained during serial clinic visits or by direct communication with patients and their cardiologists for patients who were followed up at other institutions.
Genetic analysis
For genetic analysis, peripheral blood samples were taken at the time of clinical evaluation, and they were frozen and stored at −20 °C. Deoxyribonucleic acid (DNA) was extracted using a DNA purification kit from QIAGEN Inc. (no. 51104; Hilden, Germany). In vitro amplification of genomic DNA was performed using the polymerase chain reaction (PCR). Oligonucleotide primers were used to amplify protein-encoding exons of MYBPC3. Information on primer sequences and PCR conditions is available upon request. Direct sequencing was performed and the data of sequences were analyzed on an ABI PRISM 3100-Avant Genetic Analyzer (Life Technologies, Carlsbad, CA, USA) in accordance with the manual of the manufacturer. In patients in whom mutation was identified, confirmation was obtained by re-analysis with direct sequencing from a second blood sample. Disease-causing mutations were based on presence of the mutation in all affected individuals and absence of the sequence variation in at least 200 chromosomes from healthy individuals.
Statistical analysis
Data were expressed as mean ± SD or frequency (percentage). Differences in continuous variables were assessed using Student's t-test. Pearson's chi-square test was used to compare noncontinuous variables, and Fisher's exact test was used when expected frequency was lower than 5. Survival estimates were calculated by the Kaplan–Meier method, and the log rank test was used for comparison. Statistical significance was defined by p < 0.05. Calculations were performed with SPSS Statistics 21.0 software (SPSS Inc., Chicago, IL, USA).
Results
Subject characteristics
In the 28 HCM families, a total of 61 subjects had MYBPC3 mutations (S297X in two families: three males and six females, V593fs in 23 families: 27 males and 22 females, and R945fs in three families: one male and two females) [
Lifelong left ventricular remodeling of hypertrophic cardiomyopathy caused by a founder frameshift deletion mutation in the cardiac myosin-binding protein C gene among Japanese.
A frameshift deletion mutation in the cardiac myosin-binding protein C gene associated with dilated phase of hypertrophic cardiomyopathy and dilated cardiomyopathy.
] (Fig. 1). Of the 61 subjects with mutations, 50 patients were phenotype-positive by echocardiography (maximum LV wall thickness ≥15 mm); two of them developed hypertrophy (phenotype-positive) during the follow-up period after the identification of genotype-positive. Twenty-three (46%) of those phenotype-positive patients were female. Of the 50 phenotype-positive patients, 23 patients (46%) were diagnosed because of symptoms and 27 patients (54%) were evaluated because of incidental findings, including ECG abnormalities, systolic murmur, and family screening (Table 1). At diagnosis, 28 patients (56%) had some symptoms and 6 patients (12%) had documentation of paroxysmal or chronic atrial fibrillation.
Fig. 1Flowchart of this study. HCM, hypertrophic cardiomyopathy.
Table 1Baseline characteristics in 50 HCM patients who were phenotype-positive at diagnosis.
Total (n = 50)
Male patients (n = 27)
Female patients (n = 23)
p
Age at diagnosis (years)
47 ± 17
45 ± 14
50 ± 19
0.295
Reason for diagnosis: symptoms, n (%)
23 (46%)
9 (33%)
14 (61%)
0.052
Symptoms at diagnosis, n (%)
Presence of symptoms
28 (56%)
13 (48%)
15 (65%)
0.226
Chest pain
11 (22%)
5 (19%)
6 (26%)
0.520
Palpitation
15 (30%)
9 (33%)
6 (26%)
0.577
Syncope
4 (8%)
1 (4%)
3 (13%)
0.322
NYHA functional class
0.028
I
32 (64%)
21 (78%)
11 (48%)
II
14 (28%)
6 (22%)
8 (35%)
III and IV
4 (8%)
0 (0%)
4 (17%)
Mean NYHA functional class
1.4 ± 0.6
1.2 ± 0.4
1.7 ± 0.8
0.012
Presence of AF at diagnosis, n (%)
6 (12%)
3 (11%)
3 (13%)
0.834
Maximum LV wall thickness (mm)
21 ± 5
21 ± 5
20 ± 4
0.647
Interventricular wall thickness (mm)
18 ± 5
19 ± 5
17 ± 5
0.168
Posterior wall thickness (mm)
11 ± 2
11 ± 2
10 ± 2
0.060
LV end-diastolic diameter (mm)
44 ± 7
45 ± 8
42 ± 7
0.108
Fractional shortening (%)
41 ± 9
42 ± 8
40 ± 10
0.553
Global ejection fraction (%)
66 ± 10
65 ± 9
67 ± 11
0.446
Left atrial diameter (mm)
40 ± 8
41 ± 7
40 ± 9
0.553
Dilated phase of HCM, n (%)
4 (8%)
1 (4%)
3 (13%)
0.322
Presence of LV outflow obstruction, n (%)
8 (16%)
3 (11%)
5 (22%)
0.444
Data were expressed as mean ± SD or frequency (percentage). Differences in continuous variables were assessed using Student's t-test. Pearson's chi-square test was used to compare noncontinuous variables, and Fisher's exact test was used when expected frequency was lower than 5.
HCM, hypertrophic cardiomyopathy; NYHA, New York Heart Association; AF, atrial fibrillation; LV, left ventricular.
The average ages at diagnosis were 45 ± 14 years in males and 50 ± 19 years in females. The disease penetrance in subjects aged ≤40 years old was 92% in males and 67% in females (Fig. 2A ). Fig. 2B shows Kaplan–Meier event-free curves of cardiac disease penetrance stratified by gender. The disease penetrance was age-dependent, and females showed delayed onset of LVH compared with males in subjects who were genotype-positive.
Fig. 2Disease penetrance. (A) Disease penetrance in subjects. (B) Kaplan–Meier event-free curves of cardiac disease penetrance stratified by gender.
Gender differences in patients with phenotype-positive
In patients who were phenotype-positive, female patients were more symptomatic at diagnosis than males, with mean NYHA class in female patients at diagnosis being 1.70 ± 0.77 and that in males being 1.22 ± 0.42 (p = 0.012) (Table 1). Moreover, female patients already had NYHA class III or IV symptoms at diagnosis more frequently than did males.
Echocardiographic data for the 50 patients who were phenotype-positive at diagnosis showed that females tended to have smaller LV size and a thinner LV posterior wall than those in males, but no significant differences were observed between the genders. There was no significant gender difference in the number of end-stage HCM patients or number of HCM patients with LVOTO.
Outcomes
There was no HCM-related cardiovascular event in phenotype-negative subjects with MYBPC3 mutations (n = 11). Table 2 shows the clinical events in the 50 patients who were phenotype-positive. From a longitudinal point of view by age, no significant gender difference was found for genotype-positive patients (n = 61) in HCM-related deaths, HCM-related cardiovascular events, or heart failure events. There was also no significant gender difference by age for phenotype-positive patients (n = 50) in HCM-related deaths, HCM-related cardiovascular events, or heart failure events. However, during the follow-up period after diagnosis of HCM (13 ± 8 years), female patients who were phenotype-positive had significantly more frequent heart failure events than did phenotypically affected male patients (p = 0.028) (Fig. 3). Table 3 shows the clinical complications and treatment in the 50 patients who were phenotype-positive.
Table 2Clinical events in 50 HCM patients who were phenotype-positive during follow-up period.
Fig. 3Kaplan–Meier event-free curves after diagnosis of HCM according to phenotype-positive patients for survival free from (A) HCM-related death, (B) HCM-related cardiovascular events and (C) HCM-related heart failure events. The blue curve indicates genotype-positive males and the red curve indicates genotype-positive females. HCM, hypertrophic cardiomyopathy. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
Table 3Clinical complications and treatment in 50 HCM patients who were phenotype-positive during follow-up period.
Male patients (n = 27)
Female patients (n = 23)
p
Age at final evaluation (years)
59 ± 16
61 ± 18
0.580
Presence of atrial fibrillation, n (%)
7 (26%)
11 (48%)
0.108
Presence of VT or NSVT, n (%)
7 (26%)
8 (35%)
0.496
Dilated phase of HCM, n (%)
5 (19%)
6 (26%)
0.520
Invasive treatments, n (%)
2 (7%)
3 (13%)
0.651
Medications, n (%)
ACEI or ARB, n (%)
9 (33%)
9 (39%)
0.670
Beta blockers, n (%)
14 (52%)
11 (48%)
0.777
Diuretics, n (%)
6 (22%)
10 (43%)
0.108
Data were expressed as mean ± SD or frequency (percentage). Differences in continuous variables were assessed using Student's t-test. Pearson's chi-square test was used to compare noncontinuous variables, and Fisher's exact test was used when expected frequency was lower than 5.
HCM is a primary and genetically transmitted myocardial disorder, usually caused by mutations in the genes that encode sarcomere contractile proteins and genetically transmitted with a Mendelian autosomal dominant pattern of inheritance, with a broad spectrum of morphologic features and clinical presentations [
American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines.
A systematic review and meta-analysis of genotype–phenotype associations in patients with hypertrophic cardiomyopathy caused by sarcomeric protein mutations.
]. The cardiac phenotype of HCM shows marked diversity in the degree and pattern of LVH, age of onset, and clinical course. This phenotypic heterogeneity can be established by genetic factors, including private disease-causing mutations and polymorphisms, and by environmental factors. As previously reported, gender-specific differences have been shown in acquired cardiovascular diseases, including coronary heart disease, atrial fibrillation, and stroke. However, there have been few studies in which gender-related differences in the clinical features of HCM were investigated, and knowledge about gender-related differences in cardiac manifestations in sarcomere gene mutation carriers is lacking [
Gender-specific differences in the clinical features of hypertrophic cardiomyopathy in a community-based Japanese population: results from Kochi RYOMA study.
]. Some possible explanations for this difference in diagnostic age by gender are (1) different medical screening systems, (2) clinician bias, and (3) different penetrance between the two genders. In our genotyped cohort, factors such as different medical screening systems and clinician bias were considered to be excluded as much as possible. This study confirmed a high cardiac disease penetrance in MYBPC3 mutation carriers in females and males. Furthermore, the age-dependent penetrance of LVH was even higher in men than in women. A recent large genotyped-cohort study by Page et al. reported the same finding that disease penetrance was higher in males than in females [
Cardiac myosin binding protein-C mutations in families with hypertrophic cardiomyopathy: disease expression in relation to age, gender, and long term outcome.
]. Women may have some mechanisms, such as genetic (modifier genes on the sex chromosome) and sexual hormonal factors, that prevent the development of hypertrophy, resulting in later onset of disease. Indeed, estrogen through estrogen receptor activation might modulate hypertrophic signaling in females, since estrogen treatment reduced myocardial hypertrophy in animal models [
Compared to male patients, female patients were more symptomatic at diagnosis in our genotyped cohort. Furthermore, from a longitudinal point of view by age, no significant gender difference in HCM-related adverse events was found in either genotype-positive patients or phenotype-positive patients. However, during the follow-up period from after diagnosis of HCM, once LVH had developed, female patients had significantly more frequent heart failure events than did phenotypically affected male patients. Although the reasons for these findings are not obvious, Olivotto et al. also reported in their longitudinal study that female patients were more symptomatic and that female gender was independently associated with risk of symptom progression to NYHA functional class III/IV or death from heart failure or stroke compared with male gender [
There are several limitations to be acknowledged in the present study. First, due to the retrospective design of the study, it is possible that there is a selection bias. Second, the number of subjects was small and the distribution of the MYBPC3 mutations was skewed in our genotyped cohort. Some of the statistical analyses might have been affected. Unfortunately, multivariate analysis was not used to evaluate the prognostic values of these clinical profiles because of the small sample numbers. Third, we focused on HCM patients with MYBPC3 mutations, which had been reported to be associated with delayed expression of hypertrophy and a relatively good prognosis. It is not known whether the same results would be obtained for patients with mutations in other sarcomere genes such as cardiac beta myosin heavy chain gene (MYH7) and cardiac troponin T gene. There is a recent review paper focusing on genotype–phenotype association in patients with HCM caused by sarcomere protein mutations, and some examples of general associations between genotype and penetrance are reported for MYBPC3 (late onset and higher rate of incomplete penetrance in females), MYH7 (age dependent penetrance), and cardiac troponin I gene (high rate of incomplete penetrance) [
A systematic review and meta-analysis of genotype–phenotype associations in patients with hypertrophic cardiomyopathy caused by sarcomeric protein mutations.
]. To clarify the gender differences as the important modifying factors in HCM, large-scale studies examining the relation between genotype, penetrance, disease severity, and prognosis are needed.
In conclusion, clinical manifestations differed between the genders in our genotyped cohort of HCM patients: although females with MYBPC3 mutations showed later onset of the disease, female patients were more symptomatic at diagnosis and had more frequent heart failure events once they had developed hypertrophy.
Conflict of interest
None of the authors have conflict of interest to disclose in connection with our manuscript.
Acknowledgment
This article was written based on the meeting presentation at the 16th Annual Scientific Meeting of the Japanese Heart Failure Society, Sendai, November 30–December 2, 2012.
American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines.
A systematic review and meta-analysis of genotype–phenotype associations in patients with hypertrophic cardiomyopathy caused by sarcomeric protein mutations.
Gender-specific differences in the clinical features of hypertrophic cardiomyopathy in a community-based Japanese population: results from Kochi RYOMA study.
Lifelong left ventricular remodeling of hypertrophic cardiomyopathy caused by a founder frameshift deletion mutation in the cardiac myosin-binding protein C gene among Japanese.
A frameshift deletion mutation in the cardiac myosin-binding protein C gene associated with dilated phase of hypertrophic cardiomyopathy and dilated cardiomyopathy.
Cardiac myosin binding protein-C mutations in families with hypertrophic cardiomyopathy: disease expression in relation to age, gender, and long term outcome.
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