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European Journal of Heart Failure 2008 10(9):850-854; doi:10.1016/j.ejheart.2008.06.021
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© 2008 European Society of Cardiology

Gender-specific differences in left ventricular remodelling and fibrosis in hypertrophic cardiomyopathy: Insights from cardiovascular magnetic resonance

Jeanette Schulz-Mengera,*,1, Hassan Abdel-Atya,1, Andre Rudolpha, Thomas Elgetib, Daniel Messroghlib, Wolfgang Utza, Philipp Boyéa, Steffen Bohla, Andreas Busjahnc, Bernd Hammb and Rainer Dietza

a Franz-Volhard-Klinik, Kardiologie, Charité Campus Buch, HELIOS-Klinikum Berlin, Universitätsmedizin Berlin Germany
b Institut für Radiologie, Charite Campus Mitte, Universitätsmedizin Berlin Germany
c HealthTwiSt GmbH Berlin, Germany

* Corresponding author. Schwanebecker Chaussee 50 D-13125 Berlin, Germany. Tel.: +49 30 940152903; fax: +49 30 940152919. E-mail address: jeanette.schulz-menger{at}charite.de (J. Schulz-Menger).


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Gender is an independent risk factor for heart failure mortality in hypertrophic cardiomyopathy (HCM).

Aims: To explore the interaction between gender, myocardial fibrosis and remodelling in HCM.

Methods: We studied 64 HCM patients (28 females, aged 51 ± 16 years) categorized as non-obstructive (HNCM, n=31) or obstructive (HOCM, n=33) and 60 healthy subjects (31 females, aged 43 ± 14 years). Cine imaging was performed to assess left ventricular volumes and mass. LV remodelling index (LVRI) was calculated. Extension of late gadolinium enhancement (LGE) was quantified.

Results: Females in the control group and in the HNCM group had a lower LVRI than males (control: 0.7±0.1 vs. 0.9±0.2 g/ml, <0.002; HNCM: 1.1±0.2 vs. 1.5±0.5 g/ml, p<0.001). In contrast, HOCM females had a similar LVRI compared to males (1.8±0.5 vs. 1.7±0.4 g/ml, p=ns). Thus the increase in LVRI was more pronounced in females compared to males. LGE was noted in 70% of the patients. No relation was found between the presence or the quantity of myocardial fibrosis and gender in any of the patient subgroups.

Conclusion: Our data suggest a disproportionate degree of remodelling in different forms of HCM depending on gender. Gender does not appear to influence the quantity of fibrosis as defined by LGE.

Key Words: Hypertrophic cardiomyopathy • Gender • Cardiovascular magnetic resonance • Late gadolinium enhancement

Received November 16, 2007; Revised April 23, 2008; Accepted June 9, 2008


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Epidemiological studies have shown an impact of gender on a wide range of cardiovascular disorders including development of heart failure, myocardial infarction, cardiomyopathies and arrhythmias [1-4]. Hypertrophic cardiomyopathy (HCM) is defined as left ventricular hypertrophy in the absence of another cardiac or systemic disease capable of producing the magnitude of hypertrophy evident and independent of whether or not left ventricular outflow obstruction is present [5].

The disease may be characterized by myocardial disarray and fibrosis as well. In HCM, women in particular appear to be at an increased risk of heart failure or death [6] but the exact pathophysiological grounds of these findings are unclear. Development of remodelling is known to affect prognosis. Whether these injuries are influenced by gender in HCM patients remains unclear although conceivable for several reasons. First, gender is one factor modifying the interaction between the genotype and the phenotype in HCM [7] Second, mice-models of HCM demonstrate a gender-dependent profile of left ventricular remodelling, where males exhibit an accelerated pattern of ventricular dilatation and systolic dysfunction in myosin-heavy-chain mutation, whereas in troponin-mutation the incidence of sudden cardiac death in males was higher [8]. Third, autopsy studies show that myocardial fibrosis, a substantial feature of HCM, is more pronounced in males [9]. Identifying gender-related differences in remodelling and fibrosis in HCM could help us to understand the recently recognized gender-related differences in disease presentation and prognosis in which women show a higher risk of disease progression to heart failure or death [6]. Recently, a novel index based on the relation between LV volumes and mass has been proposed to quantify left ventricular remodelling (LVRI) [10]. Since changes in left ventricular geometry are dynamic, affecting both mass and volume, combining both parameters in a single index (mass/end-diastolic volume) provides a comprehensive assessment of remodelling in HCM. Accordingly LVRI has been shown to differentiate pathological from physiological phenotypes of cardiac hypertrophy [10]. We thus aimed to investigate the value of this index for assessing changes in mass and volume using a single parameter.

Cardiovascular magnetic resonance (CMR) is the current non-invasive gold standard to assess myocardial mass and volumes due to its high observer independent reproducibility. Furthermore CMR has the capability to visualize fibrosis by applying contrast-enhanced imaging. As such, CMR is ideally suited to assess remodelling in HCM and its relation to gender.

In this study we attempt to explore the interaction between gender and left ventricular remodelling in HCM and compared it to healthy subjects. Furthermore, we investigated the relation between myocardial fibrosis and gender, including the effect of obstruction on this interaction.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Patients
Sixty-four consecutive HCM patients referred for CMR as part of their clinical evaluation were retrospectively evaluated (28 females, mean age 51±16 years) between 2002 and 2005. Six patients were planned to have septal artery embolization. Patients were categorized into non-obstructive (HNCM, n=31) or obstructive (HOCM, n=33) based on left ventricular outflow tract obstruction (area<2.7 cm2) [11]. HCM was defined based on the echocardiographic demonstration of a hypertrophied (wall thickness of 15 mm or more) non-dilated left ventricle in the absence of another related cardiac or systemic disorder [5]. Exclusion criteria were atrial fibrillation with large RR-interval-variations as well as the general contraindications for CMR.

2.2. Healthy volunteers
Sixty healthy subjects (31 females, mean age 43±14 years) with no history or clinical evidence of cardiovascular disease served as a control group. All control subjects underwent echocardiography, ECG and blood pressure evaluation.

All studies were performed under the guidelines of the local ethics committee, which approved the study and an informed consent was obtained from each subject.

2.3. Image acquisition
Images were acquired using 1.5 T magnetic resonance scanners (Sonata, Siemens Medical Solutions, Erlangen, Germany and Signa CV/i, GE medical systems, Milwaukee, USA). Localization was performed using breath-hold single-phase steady-state free precession images in 2, 3 and 4 chamber views. Retrospective-gated, steady-state free precession cine images were then acquired in short axis views covering the left ventricle (slice thickness/gap: 10/0 mm) and in long axis (2-, 3- and 4-chamber) views. In patients, late gadolinium enhancement (LGE) images covering the left ventricle were acquired 10 min after IV injection of 0.2 mmol gadolinium-DTPA (Magnevist, Schering, Germany) using a standard two-dimensional segmented inversion recovery gradient echo pulse sequence (TR:5 ms, TE: 1.3, matrix: 256x256, field of view 340-380 mm, slice thickness 10 mm with no gap, spatial resolution: 1.3x1.3x10 mm) with an inversion time optimized to null normal myocardial signal.

2.4. Image analysis
2.4.1. Volumes and mass
Endo and epicardial contours were manually drawn in systole and diastole (Fig. 1) using dedicated software (MASS 6 ®, Medis, Netherlands). End-diastolic, end-systolic volumes were measured and indexed to height and body surface area. Left ventricular mass (LVM), mass index (LVMI, indexed to height and body surface area) and left ventricular remodelling index (LVRI=LVM/EDV) [10] were calculated. Left ventricular outflow area was measured as previously described [11].


Figure 01
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  		Fig. 1 Left ventricular mass and volume quantification. The endo- and epicardial contours were manually drawn in diastole (shown) and systole (not shown) including the trabeculations and papillary muscles.

 
2.4.2. Late gadolinium enhancement (LGE)
Using the same software, myocardial areas with a signal intensity above the average plus 2 standard deviations of the normal myocardium were identified (Fig. 2 online version only) and manually traced. The total volume of LGE was expressed as a percentage of the left ventricular volume (%LGE). The ventricular apex was assessed in the long axis view.

2.5. Statistics
All statistical tests were performed using a commercially available statistical program (SPSS 11 for Macintosh, Chicago, Il, USA). Data are presented as mean±standard deviation. Continuous variables were compared using ANOVA with diagnosis and gender as between-subject variables. Mean effects as well as interaction were tested simultaneously. Non-continuous data were compared using the Chi Square test. Data were correlated using the Spearman correlation coefficient. A p value<0.05 was considered significant.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Table 1 summarizes the clinical characteristics and demography of the study population. In general, females were older than males (56 vs. 47 years, p=0.032) but not in the HOCM subgroup (59 vs. 51 years, p=0.12). Sixty nine percent of the female patients were post-menopausal compared to 23% of the control group. There were no significant differences in LVMI or LVRI between pre and post-menopausal HCM patients. None of the patients had elevated blood pressure (median values for systolic and diastolic blood pressure: 130 and 79 mmHg respectively) and the median heart rate was 66 bpm. All patients were receiving beta-blockers or calcium channel blockers at the time of the study with no significant differences in medications between males and females. Compared to HNCM, HOCM patients had elevated pressure gradient (49±42 vs. 2±4 mmHg; p=0.005). There were no significant differences between HCM patients and controls regarding height (171±10 vs. 171±9 cm; p=ns) or body surface area (1.9±0.3 vs. 1.9±0.2 m2; p=ns).


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  		Table 1 Patient demography and clinical characteristics

 
3.1. Left ventricular remodelling index
Compared to females, males had a higher LV mass index among controls (maleshealthy 68±11 vs. femaleshealthy 54±7 m2, p<0.0001) and HNCM (malesHNCM 111±29 vs. femalesHNCM 71±15 m2, p<0.0001) but not in HOCM subgroups (malesHOCM 126±30 vs. femalesHOCM 115±38 m2, p=ns). Similarly, the LV remodelling index was higher among healthy males compared to healthy females (0.9±0.2 vs. 0.7±0.1 g/ml, p=0.002). This relation was maintained in HNCM (1.5±0.5 vs. 1.1±0.2 g/ml, p=0.014) but not in HOCM (1.7±0.4 vs. 1.8±0.5 g/ml, p=ns) patients. As indicated by a significant interaction between diagnosis and sex (p=0.037), the increase in LV remodelling index was more pronounced in females compared to males for HOCM only.

Only men showed a significant inverse relation between age and LV mass (–0.36, p=0.036). In a linear regression analysis model including ejection fraction, type of HCM (obstructive or non-obstructive), gender and age, only gender and type of HCM were independent predictors (p<0.0001) of LV remodelling index.

3.2. Late gadolinium enhancement
LGE was observed in 70% of the patients. The incidence of LGE was not significantly different in females (75%) compared to males (66%), p=0.47. Similarly, the % LGE did not show gender-related differences in the group as a whole (males: 7.7±10%, females: 7.7±8%, p=ns,) or in the subgroups of HNCM and HOCM. The pattern and distribution of LGE did not differ between gender groups with the right ventricular insertion points affected in 72% of the cases. LGE lesions were intramural and characteristically spared the subendocardium. Eighty-four percent of the patients with positive LGE had their lesions in the segment of maximum wall thickness. In the group as a whole, LGE was significantly related to LVM (r=0.36, p=0.012). However when gender was taken into account, this relation remained significant in men (p=0.013) but not in women (p=0.098). Age was inversely related to the absolute (–0.48, p=0.006) and % LGE (–0.36, p=0.038) in males but not in females. There was no significant correlation between LVOT area and the amount of LGE in any patient subgroup depending on gender.


   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
In this report we evaluated the interaction between gender, myocardial fibrosis as assessed by CMR-LGE and remodelling in HCM patients.

A number of studies have attempted to explore the effect of gender on disease phenotype in HCM [7,12,13], a challenging task because gender affects the phenotype of normal hearts as well [14]. Therefore we designed our study to include healthy subjects, with the aim of elucidating the HCM-specific effects of gender on cardiac phenotype and remodelling. To describe the change in LV-geometry we quantified the left ventricular remodelling index. This index was recently introduced and proved successful in characterizing different cardiomyopathies with varying phenotypes [10]. The LVRI takes into account the relation between myocardial mass and volume and is known as an indicator of LV-adaptation [10]. Rather than considering the ‘absolute’ gender differences in LV remodelling in HCM patients, we evaluated the ‘relative’ difference between HCM and the normal state in each gender group. The analysis yielded the interesting finding that HOCM females appeared to experience a significantly larger degree of remodelling than their male counterparts. This extensive remodelling appears to be mainly determined by the relatively increased myocardial mass in this patient subgroup. The underlying mechanism is not clear but it has been shown that the female heart responds to increased load with extensive hypertrophy, an adaptive mechanism aimed at hindering cavity dilatation and preserving systolic function [15]. Exhaustion of this adaptive mechanism may then explain the higher risk of progression to advanced heart failure in HCM females recently shown by Olivotto et al. [6]. Our results suggest gender-specific enhanced remodelling as one possible mechanism for the gender-specific prognostic profile in HCM patients. HCM women however, were significantly older than their male counterparts yet we do not believe age confounded our gender-specific findings for two reasons. First, Maron et al. [7] found that age was in fact inversely related to LV mass in females. Accordingly one would expect that our ‘older’ female population should exhibit a reduction instead of the increase in LV mass we noted. Second, Maceira et al. [16] found no relation between age and LV mass in healthy volunteers rendering the effect of age on our findings highly unlikely.

In agreement with previous studies we identified LGE in 70% of HCM patients [17,18] Myocardial fibrosis is most likely the underlying injury of LGE in HCM, which has been shown to correlate with the severity of hypertrophy and to the traditional risk factors [17,19,20]. Interestingly, we did not find gender-related differences in the incidence or extent of LGE in our series. In contrast, in their large autopsy series, Varnava et al. [9] found that microscopic fibrosis was greater in HCM males compared to females. Furthermore, in a mouse model of hypertensive left ventricular hypertrophy, androgen contributed to more hypertrophy and fibrosis in males [21]. The reason for the discrepancy between our findings and these reports is not clear but HCM is a complex disorder in which the interaction between the genetic and phenotypic patterns can be influenced by factors such as modifying genes, environment, age and gender. Specifically, in contrast to our patient population, the autopsy series of Varnava et al. investigated patients dying from end stage heart failure or sudden cardiac death. Furthermore, because women were older in our study we cannot exclude the possibility that they were in fact in a different disease stage compared to males. It is also well-known that HCM women are in general diagnosed later than males [6]. These factors may have acted to cancel-out the differences in fibrosis one might have otherwise encountered.

The lack of correlation between LVH and fibrosis in females in contrast to males is intriguing and further underlines the fact that LVH and fibrosis are two ‘separate’ features of HCM [22] and that gender appears to exert a phenotype-modifying effect in this setting. Finally, the results imply that some of the known relations in HCM are gender-dependent. For example the direct relation between LVH and myocardial fibrosis [18] as well as the inverse relation between LVH and age [23] appear to hold true only in males.

This study has some limitations. We did not assess the possible effect of hormone replacement therapy in our post-menopausal subgroup. In addition, since this study was conducted in a tertiary referral centre, we are aware that our results may only apply to similar settings. Since CMR was performed as part of the clinical evaluation of these patients, only one CMR study was performed. Therefore, we were not able to evaluate the progression of fibrosis and morphological changes longitudinally in our patient population. Further studies are definitely warranted to address this issue.

In conclusion, gender is a significant factor influencing the unique interaction between tissue injury and remodelling in hypertrophic cardiomyopathy. Future studies with larger numbers of patients are warranted to elucidate the prognostic impact of these findings.


   Acknowledgements
 
The authors would like to thank the referring clinicians, our study nurse Melanie Bochmann and our technicians led by Kerstin Kretschel.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
1 Both authors contributed equally to the manuscript. Back


   References
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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