The influence of age on gender-specific differences in the left ventricular cavity size and contractility in patients with hypertrophic cardiomyopathy

International Journal of Cardiology 88 (2003) 11–16 www.elsevier.com / locate / ijcard

The influence of age on gender-specific differences in the left ventricular cavity size and contractility in patients with hypertrophic cardiomyopathy a, b b a Pawel« Petkow Dimitrow *, Danuta Czarnecka , Kalina Kawecka-Jaszcz , Jacek S. Dubiel a

´ , Poland 2 nd Department of Cardiology, Jagiellonian University School of Medicine, ul. Kopernika 17, 31 -501 Krakow b ´ , Poland 1 st Department of Cardiology, Jagiellonian University School of Medicine, Krakow Received 5 May 2001; received in revised form 15 October 2001; accepted 30 November 2001

Abstract Background: The aim of the study was to assess gender-specific differences in left ventricular cavity size, contractility and left ventricular outflow tract obstruction in younger and older subgroups of patients with hypertrophic cardiomyopathy. Methods: We studied retrospectively 153 referred patients with hypertrophic cardiomyopathy (89 males and 64 females). The echocardiographically measured left ventricular end-systolic, end-diastolic dimensions, fractional shortening and occurrence of left ventricular outflow tract gradient were compared between sexes in subgroups of patients #50 and .50 years of age. Results: In younger patients with hypertrophic cardiomyopathy, left ventricular end-diastolic and end-systolic dimensions were significantly smaller in females than males (41.965.8 vs. 44.765 mm P,0.01 23.465 vs. 25.265.4 mm P,0.05, respectively). Fractional shortening was comparable in both sexes (44.767.5 vs. 43.768.2% P.0.05). The left ventricular outflow tract gradient occurred in females as frequently as in males (13.3 vs. 17.6% P.0.05). In older patients with hypertrophic cardiomyopathy, left ventricular end-diastolic and end-systolic dimensions were also significantly smaller in females than males (42.566 vs. 46.363.2 mm P,0.02; 25.764.8 vs. 28.663.7 mm P,0.01, respectively). In contrast to the younger group, the fractional shortening was significantly higher in females than males (44.466.8 vs. 38.267.3% P,0.02). The left ventricular outflow tract gradient occurred in females more frequently than in males (63.2 vs. 20.8% P,0.02). Conclusions: In patients with hypertrophic cardiomyopathy, the gender-based differences in the absolute value of left ventricular cavity size persisted with aging. In older females left ventricular contractility was higher and left ventricular outflow tract gradient occurred more frequently than in males. In younger patients with hypertophic cardiomyopathy these sex-based differences were absent. The gender-specific differences in the parameters of left ventricular systolic function became apparent with increasing age.  2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Hypertrophic cardiomyopathy; Gender; Left ventricular cavity size; Gradient

1. Introduction An age-related difference in left ventricular morphology between females and males has been demonstrated most recently in a transgenic mouse model of hypertrophic cardiomyopathy [1]. Males began to display left ventricular dilation and left ventricular *Corresponding author. Fax: 148-12-421-4029. E-mail address: [email protected] (P.P. Dimitrow).

systolic dysfunction with aging. In contrast, females at the same age of 10 months continued to present with left ventricular concentric hypertrophy with preserved left ventricular systolic function [1]. This difference may be accounted for the fact that males developed myocardial fibrosis earlier, more frequently and more pronouncedly than female mice with transgenic hypertrophic cardiomyopathy [2]. Accordingly in human hypertrophic cardiomyopathy subjects, the extent of myocardial fibrosis was greater in

0167-5273 / 02 / $ – see front matter  2002 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016 / S0167-5273( 02 )00323-6

P.P. Dimitrow et al. / International Journal of Cardiology 88 (2003) 11 – 16

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males than females [3]. Replacement fibrosis has been proposed as a potential reason for left ventricular remodeling in hypertrophic cardiomyopathy [4], which developed preferably in male mice with hypertrophic cardiomyopathy [1]. Previous studies in patients with hypertrophic cardiomyopathy showed that the septal and left ventricular wall thickness were similar between sexes, whereas the age of symptom onset was later in females than males both in referred [5–8] and unselected, nonreferral [9] population. Moreover, females had a smaller left ventricular cavity size in comparison with males [8–10]. Left ventricular contractility was comparable between sexes in one study [10] and increased in females in another study [7]. However, to our knowledge, the influence of age on gender-based comparison of echocardiography parameters has not been reported in human subjects with hypertrophic cardiomyopathy, yet. Accordingly, the aim of our study was to compare left ventricular cavity size, contractility and frequency of left ventricular outflow tract gradient between sexes in subgroups of younger and older patients.

2. Methods

2.1. Study population Between 1982 and 2001, 153 consecutive patients with hypertrophic cardiomyopathy fulfilling the diagTable 1 Comparison of treatment, heart rate and blood pressure between sexes Males (n / %)

Females (n / %)

Younger patients Beta-blockers Verapamil Diuretic agents with vasodilators Heart rate (/ min) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg)

38 (51.4%) 35 (47.3%) 1 (1.3%) 6466 12169 7868

23 (51.2%) 22 (48.8%) 0 (0%) 6665 118610 7666

NS NS NS

Older patients Beta-blockers Verapamil Diuretic agents with vasodilators Heart rate (/ min) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg)

6 (40%) 7 (46.7%) 2 (13.3%) 6766 124612 8368

8 (42.1%) 9 (47.4%) 2 (10.5%) 6465 121610 7967

NS NS NS NS NS NS

B-B, Beta-blockers; NS, non significant; V, verapamil.

NS NS

nostic criteria of hypertrophic cardiomyopathy [11,12] were referred for evaluation to our institutions. The history of these patients was reviewed retrospectively. Among 153 patients (aged 18–78 years) there were 89 males and 64 females. At the time of echocardiographic evaluation, patients were on treatment (mainly on verapamil 240–480 mg / day or propranolol 60–120 mg / day). Drugs, which may have influenced left ventricular outflow tract gradient were compared between sexes (Table 1). The patients were divided into subgroups according to age: younger patients #50 and older patients .50 years.

2.2. Study protocol Echocardiographic studies were performed using Hewlett-Packard ultrasound apparatus (Andover, MA, USA). Each patient underwent M-mode and twodimensional echocardiographic study, followed by pulsed and continuous-wave Doppler ultrasound study. The following parameters were measured from M-mode echocardiograms: left ventricular end-diastolic diameter, left ventricular end-systolic diameter and percent of fractional shortening as an index of left ventricular contractility status. Additionally, the left ventricular end-systolic and end-diastolic dimensions were indexed to body surface area. The magnitude of left ventricular outflow tract gradient at rest was estimated with continuous-wave Doppler using the simplified Bernoulli equation. Left ventricular outflow tract obstruction was considered to be marked when the gradient was $50 mmHg. The limit value of significant left ventricular outflow tract gradient was increased from 30 (common borderline value) to 50 mmHg because this more restrictive criterion has been usually an indication for myotomy–myoectomy in the presence of severe symptoms refractory to drugs. Moreover, it seems that the higher borderline value of left ventricular outflow tract gradient may be a more reliable marker of significant obstruction in the face of marked spontaneous fluctuations of left ventricular outflow tract gradient.

2.3. Statistical analysis Data are expressed as means6S.D. Statistical analyses were performed using unpaired Student’s

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t-test. Proportions were compared using Fisher’s exact test. Differences were considered significant when P,0.05.

3. Results The respective drug classes influencing left ventricular outflow tract gradient and contractility were used with the comparable frequency between male and female patients with hypertrophic cardiomyopathy (Table 1). The heart rate, systolic and diastolic blood pressure did not differ between sexes (Table 1). In younger patients, the left ventricular end-diastolic and end-systolic dimensions were significantly smaller in females than males, while fractional shortening was comparable between sexes (Table 2). Left ventricular cavity size indexed to body surface area was similar between sexes (Table 2). The left ventricular outflow tract gradient was as frequent in females as in males (Table 2). The septum and posterior wall thickness did not differ between sexes (Table 2). In older patients, the left ventricular end-diastolic Table 2 Gender-based comparison of echocardiographic parameters Females

Males

P,

Younger patients LVD (mm) LVS (mm) LVD/ BSA (mm / m 2 ) LVS / BSA (mm / m 2 ) FS (%) LVOTG, n (%) Septum thickness (mm) Posterior wall thickness (mm)

41.965.8 23.465 25.363.7 14.163.1 44.767.5 6 (13.3%) 22.565.8 12.165.3

44.765 25.265.4 2463.1 13.563.2 43.768.2 13 (17.6%) 23.666.0 12.363.1

0.01 0.05 NS NS NS NS NS NS

Older patients LVD (mm) LVS (mm) LVD/ BSA (mm / m 2 ) LVS / BSA (mm / m 2 ) FS (%) LVOTG, n (%) Septum thickness (mm) Posterior wall thickness (mm)

42.566 25.764.8 24.963.5 13.962.4 44.466.8 12 (63.2%) 22.564.7 12.162.6

46.363.2 28.663.7 24.862.1 15.362.1 38.267.3 3 (20%) 24.265.2 12.562.5

0.02 0.01 NS 0.1 0.02 0.02 NS NS

BSA, Body surface area; FS, shortening fraction; LVD, left ventricular end diastolic diameter; LVS, left ventricular end systolic diameter; LVOTG, left ventricular outflow tract gradient occurrence; NS, non significant.

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and end-systolic dimensions were significantly smaller in females than males. In the contrast to younger patients, fractional shortening was significantly reduced in males in comparison with females among older patients (Table 2). End-systolic left ventricular dimension indexed to body surface area had a tendency to be greater in males than females (Table 2). The left ventricular outflow tract gradient occurred more frequently in females than males (Table 2). The septum and posterior wall thickness did not differ between sexes (Table 2).

4. Discussion Cross-sectional echocardiographic analyses of large population of patients with hypertrophic cardiomyopathy (HCM) encompassing a broad age spectrum have documented morphologic differences between young and older patients [7,13–16]. Left ventricular wall thickness is generally much milder in patients of more advanced age than in the young [7,13–16]. There are two possible explanation for this phenomenon. Firstly, young patients with particularly marked left ventricular hypertrophy probably have a higher rate of premature sudden death. Consequently, patients with massive left ventricular hypertrophy may be under-represented in subgroup of older HCM patients. Secondly, it is suggested that gradual left ventricular remodeling involving some degree of wall thinning could occur slowly over decades [4,16]. The regression of left ventricular hypertrophy may be associated with the enlargement of left ventricular cavity and systolic dysfunction in some patients during longitudinal observation [17]. However, in this study only an average 4-year follow-up was available. To support the hypothesis of left ventricular remodeling, prospective, long-term, longitudinal studies are needed. According to Marom and Spirito [4] the serial two-dimensional echocardiographic studies of left ventricular morphology in the same patients are not yet possible over a sufficiently long period of time (20–30 years). Similar in our study we did not have such a long-term echocardiographic follow-up in most of patients. Therefore, we cannot provide a definite explanation for these age-related differences in left ventricular morphology among patients with hypertrophic cardiomyopathy.

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However, we suspected that gender might partially influence the left ventricular remodeling process in hypertrophic cardiomyopathy based upon observations from a transgenic mice model of hypertrophic cardiomyopathy. The short-lasting life of mice in comparison with human subjects provides an opportunity to obtain definite findings during 1-year follow-up. Age-related differences in left ventricular morphology between females and males have been demonstrated in the transgenic mouse model of hypertrophic cardiomyopathy [1]. Males began to display left ventricular dilation and systolic dysfunction with aging. In contrast, females at the same age of 10 months continued to present with left ventricular concentric hypertrophy with preserved left ventricular systolic function [1]. In transgenic mice [2], males developed myocardial fibrosis earlier, more frequently and more pronouncedly than females. Accordingly in human hypertrophic cardiomyopathy subjects, the extent of myocardial fibrosis was greater in males than females [3]. Fibrosis replacing myocardial contractile fibres is proposed as a mechanism of left ventricular remodeling which deteriorates systolic function and enlarged left ventricular cavity [4]. In our previous study [10] in overall group of patients with hypertophic cardiomyopathy females presented with smaller left ventricular cavity however left ventricular systolic function was comparable between sexes. In the present study in a larger group of patients, we made a gender-based comparison separately in younger and older subgroups of patients with hypertrophic cardiomyopathy. In younger patients the systolic function and left ventricular cavity size normalised for body surface area were similar between sexes. In older patients, males presented with significantly decreased left ventricular contractility and a tendency to larger left ventricular endsystolic dimensions indexed to body surface area in relation to females. In a previous study using magnetic resonance imaging among patients with hypertrophic cardiomyopathy [8], the smaller left ventricular volumes in females than males were present even after volume normalisation for body surface area. The statistical difference was more powerful for the left ventricular end-systolic than end-diastolic volumes. Unfortunately the mean age was not compared between sexes in this preliminary report [8]. We suspect that such significant gender-specific

differences in the normalised left ventricular volume may be influenced by the potential difference in age. The second reason for the difference between our non significant and their significant findings may be derived from the fact that magnetic resonance imaging measured three-dimensional volume (more accurate method) which may augment the differences from one-dimensional echocardiographic measurements (less accurate method). Our study revealed that in older patients with hypertrophic cardiomyopathy, the significant left ventricular outflow tract gradient occurred predominantly in females. In younger patients these genderspecific differences were not present. Our observation may be in line with evidence from the previous study [9] where left ventricular outflow tract gradient occurred more frequently in females, who were significantly older than males (59 versus 47 years on average). Respectively, the females from this report seem to be age-matched to our older subgroup of females whereas males from above citation seem closer age-related with our younger subgroup of males. Importantly, in another study [18] males with hypertrophic cardiomyopathy predominated in small group of patients in whom left ventricular outflow tract gradient decreased at follow-up. A long followup in larger group of patients with hypertrophic cardiomyopathy is required to verify the hypothesis that in males left ventricular outflow tract gradient rather decreases during life whereas in females the obstruction usually does not disappear with aging. The clinical implication from the present study is a hypothesis about different therapeutic approach dependent on the sex. It seems reasonable to speculate that in males with non obstructive hypertrophic cardiomyopathy with aging inhibitor of angiotensin-1 converting enzyme should be introduce. This drug may hypothetically prevent the unfavorable, more dynamic left ventricular remodeling. In males with obstructive hypertrophic cardiomyopathy and severe symptoms refractory to drugs, the non-pharmacological method to relieve left ventricular outflow tract obstruction should be carefully chosen. We speculate that in males myotomy–myoectomy may be more beneficial than percutaneous transluminal septal myocardial ablation. Data accumulated over 30 years experiences indicate that myotomy–myoectomy provides a long-lasting, substantial and persistent symp-

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tom improvement [19,20]. In contrast, the available follow-up after percutaneous transluminal septal myocardial ablation is shorter and some reports [21,22] warn against impairment of left ventricular systolic function during follow-up. Interestingly, left ventricular end-diastolic diameter decreased immediately after percutaneous transluminal septal myocardial ablation but it increased after 3 months [22]. It is possible that the infarct-related remodeling may unfavorably add to the more dynamic natural left ventricular remodeling observed in male mice with hypertrophic cardiomyopathy [1]. All these hypotheses need confirmation in larger, long-lasting, prospective study.

5. Study limitations The patient referral and selection biases may have an impact on our results. The referred patients were treated prior to our examination. However, the mode of treatment was similar in both sexes and therefore we believe that our comparison seems reliable. Unfortunately, the retrospective type of our study did not allow us to obtain left ventricular cavity dimensions before treatment in some patients. The transgenic mice with hypertrophic cardiomyopathy had the same mutation whereas our population was affected by different types of mutation. The genetic heterogeneity of the our population may also lead to bias in the results. However, the type of mutation was not the only factor influencing phenotypic expression of hypertrophic cardiomyopathy. Family members with hypertrophic cardiomyopathy, despite the common genetic substrate, may exhibit markedly diverse and distinct expressions of natural history of their disease [23,24]. Dissimilar clinical evolution included progression to end-stage heart failure or sudden death [23,24]. On the other side, a variety of mutations in gene have been reported in patients with hypertophic cardiomyopathy in the end-stage [25,26]. Therefore, it is unlikely that the propensity to develop this clinical course is attributable to any particular HC-causing mutant gene. The development of left ventricular wall thinning and systolic dysfunction probably represents a more complex phenomenon influenced by modifier genes [27]. The gender may also modify the pheno-

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typic expression of hypertrophic cardiomyopathy [28]. A small number of older patients is the next limitation of our study and it may be accounted for the fact that a tendency to greater left ventricular cavity normalised to body surface area in males did not reach statistical significance (possibility of beta error).

6. Conclusions In patients with hypertophic cardiomyopathy, the gender-based differences in the absolute value of left ventricular cavity size persisted with aging. In older females left ventricular contractility was higher and left ventricular outflow tract gradient occurred more frequently than in males. In younger patients with hypertophic cardiomyopathy these sex-based differences were absent. The gender-specific differences in the parameters of left ventricular systolic function became apparent with increasing age.

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Editorial comment

The impact of gender on left ventricular remodeling in hypertrophic cardiomyopathy A. Varnava* Department of Cardiology, London Chest Hospital, Bonner Road, London E2 9 JX, UK Received 18 March 2002; accepted 14 May 2002

Original PII of article: S0167-5273(02)00323-6 *Tel.: 144-0208-980-4433; fax: 144-0208-983-2278. E-mail address: [email protected] (A. Varnava).

The importance of gender in determining the severity of certain diseases is well established. It is clear that the risk of atherosclerotic disease is

0167-5273 / 02 / $ – see front matter  2002 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016 / S0167-5273( 02 )00322-4