Impact of gender on the left ventricular cavity size and contractility in patients with hypertrophic cardiomyopathy

International Journal of Cardiology 77 (2001) 43–48 www.elsevier.com / locate / ijcard

Impact of gender on the left ventricular cavity size and contractility in patients with hypertrophic cardiomyopathy a, b Pawel« Petkow Dimitrow *, Danuta Czarnecka , Jacek A. Strojny c , Kalina Kawecka-Jaszcz b , Jacek S. Dubiel a 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 c ´ , Poland Institute of Statistics, Agricultural Academy, Krakow Received 4 July 2000; accepted 13 September 2000

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 patients with hypertrophic cardiomyopathy. Methods: We studied retrospectively 129 referred patients with hypertrophic cardiomyopathy (77 males and 52 females). The echocardiographically measured left ventricular end-systolic, end-diastolic dimensions, fractional shortening and occurrence of left ventricular outflow tract gradient $30 mmHg were compared between sexes. Logistic regression analysis was used to calculate the predictive values of left ventricular dimensions and contractility for left ventricular outflow tract obstruction for each gender separately. Results: Left ventricular end-diastolic and end-systolic dimensions were significantly smaller in females than males (41.765.3 vs. 45.164.9 mm, P50.0003; 23.1644 vs. 25.665.3 mm, P50.007 respectively). On the contrary, the value of fractional shortening was comparable in both sexes (44.767.3 vs. 43.667.9%, P.0.05). The left ventricular outflow tract gradient occurred in females as frequently as in males (28.8 vs. 33.8%, P.0.05). By logistic regression analysis the predictors of left ventricular outflow tract gradient in females were left ventricular end-systolic diameter (relative risk50.74; confidence interval (CI) 0.61 to 0.91; P50.0038), left ventricular end-diastolic diameter (relative risk50.82; CI 0.72 to 0.96; P50.0061) and fractional shortening (relative risk51.11; CI 1.01 to 1.22; P50.036). The most potent predictor appeared to be left ventricular end-systolic dimension. In males none of these parameters identified patients with left ventricular outflow tract obstruction. Conclusions: Females with hypertrophic cardiomyopathy featured smaller left ventricular cavity size, which predisposed to left ventricular outflow tract obstruction (the most potent predictor of left ventricular outflow tract obstruction was left ventricular end-systolic dimension). Higher left ventricular contractility also determined left ventricular outflow tract gradient occurrence in females with hypertrophic cardiomyopathy. In males despite a larger left ventricular cavity size the left ventricular outflow tract obstruction occurred with a similar frequency as in females. Left ventricular outflow tract obstruction was not predicted by left ventricular cavity size or contractility in males.  2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Hypertrophic cardiomyopathy; Gender; Left ventricular cavity size

1. Introduction In patients with hypertrophic cardiomyopathy, the small left ventricular cavity size and occurrence of *Corresponding author. Fax: 148-12-421-3732. E-mail address: [email protected] (P.P. Dimitrow).

left ventricular outflow tract gradient have been recently identified as risk factors of sudden death [1–3]. Previous studies in patients with hypertrophic cardiomyopathy showed that the septal and left ventricular wall thickness were similar between sexes, whereas age of symptom onset was later in

0167-5273 / 01 / $ – see front matter  2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 00 )00401-0

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females than males both in referred [4–7] and unselected, nonreferral [8] populations. Recently, it was reported in patients with hypertrophic cardiomyopathy, that females had smaller left ventricular cavity size at echocardiography in comparison to males [7,8]. Additionally, females presented more frequently with left ventricular outflow tract gradient than males [8]. In patients with left ventricular hypertrophy (predominantly secondary to hypertension) the small size of left ventricular cavity, hypercontractility and female sex predisposes to provocable left ventricular outflow tract gradient [9]. Therefore, we decided to compare left ventricular cavity dimension between sexes and to assess a potential influence of left ventricular cavity size and contractility on left ventricular outflow tract gradient occurrence in a gender-divided group of referred patients with hypertrophic cardiomyopathy.

2. Methods

2.1. Study population Between 1982 and 1999, 130 consecutive patients fulfilling the diagnostic criteria of hypertrophic cardiomyopathy [10,11] were referred for evaluation to our institutions. The history of these patients was reviewed retrospectively. The exclusion criterion i.e. left ventricular cavity dilatation (left ventricular enddiastolic dimension .55 mm) was present in one patient. Among 129 patients (aged 20–78 years) there were 77 males and 52 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 influence left ventricular outflow tract gradient were compared between sexes (Table 1).

2.2. Study protocol Echocardiographic studies were performed using a Hewlett-Packard ultrasound apparatus (Andover, Massachusetts, USA). Each patient underwent Mmode and 2-dimensional echocardiographic study, followed by pulsed and continuous-wave Doppler ultrasound study. The following parameters were measured from M-mode echocardiograms: left ven-

tricular end-diastolic diameter, left ventricular endsystolic diameter and percent of fractional shortening as an index of left ventricular contractility status. Additionally the left ventricular end-systolic and enddiastolic dimensions were indexed to body surface area. The magnitude of resting left ventricular outflow tract gradient was estimated with continuouswave Doppler using the simplified Bernoulli equation. Significant left ventricular outflow tract obstruction was considered to be present when the gradient was $30 mmHg.

2.3. Statistical analysis Data are expressed as means6S.D. Statistical analyses were performed using unpaired Student’s t-test. Proportions were compared using Fisher’s exact test. The linear regression analysis according to Pearson was used to correlate left ventricular outflow tract gradient (as continuous variable) with left ventricular dimensions. Logistic regression analysis using SPSS statistical package was performed to assess independent predictors of dichotomous variable left ventricular outflow tract gradient (as a categorical variable) in female and male subgroups separately. The dependent variable was dichotomised as follows: left ventricular outflow tract gradient $30 mmHg was assigned a value of 1, whereas left ventricular outflow tract gradient ,30 mmHg was coded 0. The independent variables (left ventricular end-diastolic, end-systolic dimension and fractional shortening) were all continuous. The goodness-of-fit of logistic regression for each variable was calculated using the Nagelkerke 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 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). The left ventricular end-diastolic and end-systolic dimensions were significantly smaller in females than males, while fractional shortening was comparable

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Table 1 Comparison of treatment, heart rate and blood pressure between sexes

Beta-blockers Verapamil Diuretic agents added to B-B a or V a Diuretic agents with vasodilators Heart rate (/ min) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) a

Males (n / %)

Females (n / %)

42 (54.5%) 32 (41.5%) 7.8 (6.5%) 3 (3.8%) 6566 121611 7968

27 (51.9%) 23 (44.2%) 5 (9.6%) 2 (3.8%) 6465 119610 7766

NS a NS NS NS NS NS NS

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

between sexes (Table 2). Since the females had smaller body surface area than males, left ventricular cavity size indexed to body surface area was similar in both sexes (Table 2). The left ventricular outflow tract gradient was as frequent in females as in males (Table 2). In females with left ventricular outflow tract gradient, left ventricular cavity size was smaller and fractional shortening was greater than in females without left ventricular outflow tract gradient (Table 2). In males left ventricular dimension and contractility were comparable between those with and without left ventricular outflow tract obstruction (Table 2). The linear regression showed the significant correlation between left ventricular outflow tract gradient and left ventricular dimension only in females (r52 0.52, P50.00006 for left ventricular end-systolic diameter and r520.44, P50.001 for left ventricular end-diastolic diameter). The logistic regression analysis confirmed the association between left ventricular

outflow tract obstruction and parameters describing left ventricular cavity size and contractility in females. Respectively, the predictors of left ventricular outflow tract gradient in females were left ventricular end-systolic diameter (relative risk50.74; confidence interval (CI) 0.61 to 0.91; P50.0038), left ventricular end-diastolic diameter (relative risk50.82; CI 0.72 to 0.96; P50.0061) and fractional shortening (relative risk51.11; CI 1.01 to 1.22; P50.036). The most potent predictor appeared to be left ventricular end-systolic dimension (the best value of goodnessof-fit Nagelkerke test50.308). In males none of these parameters predicted left ventricular outflow tract obstruction by logistic regression analysis.

4. Discussion The smaller left ventricular end-diastolic dimension in females than in males has been demonstrated

Table 2 (a) Gender-based comparison of echocardiographic parameters; (b) comparison of echocardiographic parameters in obstructive and nonobstructive patients with hypertrophic cardiomyopathy in both sexes* (a)

Females

Males

P5

LVD (mm) LVS (mm) BSA (m 2 ) LVD/ BSA (mm / m 2 ) LVS / BSA (mm / m 2 ) FS (%) LVOTG n (%)

41.765.3 23.164.4 1.6960.15 24.963.6 13.962.8 44.767.3 15 (28.8%)

45.164.9 25.665.3 1.8760.14 24.363.1 13.863.1 43.667.9 26 (33.8%)

0.0003 0.007 0.0001 NS NS NS NS

(b)

Females LVOTG (1)

Females LVOTG (2)

Males LVOTG (1)

Males LVOTG (2)

LVD LVS FS

38.365.5 19.964 48.267.4

43.164.6* 24.563.9* 43.366.8*

45.564.1 2665.2 43.267.8

44.915.2 25.365.3 43.867.9

* P,0.05 females with LVOTG versus females without LVOTG. 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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by echocardiography in unselected patients with hypertrophic cardiomyopathy [8]. In the present study among the referred, therefore selected patients with hypertrophic cardiomyopathy, females had a smaller left ventricular cavity both at systole and diastole in comparison to males. Since body surface area was smaller in females than males, the values of left ventricular dimension indexed to body surface area did not differ significantly between sexes in our patients. However we suggest that the absolute rather than normalised values of left ventricular dimension are more important for left ventricular outflow tract gradient generation. The importance of absolute left ventricular end-systolic dimension in induction of left ventricular outflow tract gradient in patients with hypertrophic cardiomyopathy was demonstrated in a study by Sherrid et al. [12]. In their study [12], left ventricular outflow tract gradient (triggered by midventricular, not subaortic, ejection flow acceleration) was eliminated by drugs with a parallel increase in left ventricular end-systolic dimension. In a study using magnetic resonance imaging among patients with hypertrophic cardiomyopathy [7], the smaller left ventricular volumes in females than males were still present after left ventricular volume normalisation for body surface area. We suspect that such preservation of differences in left ventricular volume may be associated with the fact that magnetic resonance imaging measured 3-dimensional volume which may augment the differences from 1-dimensional echocardiographic measurements. A potential role of small left ventricular cavity size in predisposing to the induction of left ventricular outflow tract gradient in females has not been investigated earlier [7,8]. In our study the decrease of left ventricular cavity dimension predicted left ventricular outflow tract obstruction in females, whereas in males such relationship was not observed. Moreover, the greater left ventricular contractility was associated with left ventricular outflow tract obstruction, but only in females. In secondary left ventricular hypertrophy due to hypertension, left ventricular outflow tract gradient provocation was associated with small left ventricular cavity size and increased left ventricular contractility [9]. Our study confirmed such relationship in primary left ventricular hyper-

trophy indicating that left ventricular end-systolic dimension was the most potent predictor of occurrence of left ventricular outflow tract obstruction in females. In a previous study [12] left ventricular outflow tract gradient was eliminated by drugs with parallel increase in left ventricular end-systolic dimension. Similarly, decreased left ventricular outflow tract gradient after myectomy was associated with a sole increase of left ventricular end-systolic dimension, which reduced left ventricular hypercontractility [13]. Importantly, this association involved patients with obstructive hypertrophic cardiomyopathy in whom area of septal resection did not extend to that left ventricular level, where cavity dimensions were measured [13]. Moreover, myotomy alone, not myectomy, has also been reported to decrease left ventricular outflow tract obstruction [14,15]. Nakatani et al. [13] suggested that, once continuity of fibre is disrupted in one area, fibre shortening may be reduced even in a remote area. This may explain why ventricular contraction (which is away from the myectomy site) was reduced after myectomy and its decrease may contribute to relief of left ventricular outflow tract obstruction [13]. Moreover, some patients show significant residual left ventricular outflow tract gradient after myectomy in spite of substantial left ventricular outflow tract enlargement [14,16,17]. These observations support the suggestion that mechanisms other than left ventricular outflow tract widening may contribute to reduced left ventricular outflow tract gradient. In Nakatani et al.’s study [13] multiple stepwise linear regression analysis showed that a change in midventricular fractional area yielded the best correlation with the change in left ventricular outflow tract gradient. Thus, left ventricular contraction determining ejection flow acceleration and hydrodynamic forces [18] may effectively influence left ventricular outflow tract gradient occurrence. Our study confirmed such relationship in female patients. The present study did not confirm the observation that the left ventricular outflow tract gradient more frequently occurred in females as it was demonstrated in an unselected hypertrophic cardiomyopathy cohort [8]. This may result from the fact that in the present study, a different population i.e. selected by referral

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bias (so-called ‘worse’ segment of hypertrophic cardiomyopathy disease spectrum [19]) was investigated. Apart from the differences in study populations, different pharmacological treatment may also be responsible for the opposite result in the present study as compared to that of Maron et al. [8]. In the study of Pelliccia et al. [20] among a referred population (similar to ours), there were no gender differences in the prevalence of left ventricular outflow tract obstruction, which is in line with our results. To our knowledge, the new information from the present study is that left ventricular outflow tract obstruction is predicted by small left ventricular cavity and hypercontractility only in females, whereas, in males such factors do not determine left ventricular outflow tract obstruction. The mechanism of left ventricular outflow tract gradient induction is complex and mitral valve apparatus also contributes to obstruction [21,22] by systolic anterior motion of mitral leaflet. In a previous study [21] assessing morphometrically mitral valve specimens (so-called gold standard) it was demonstrated that enlarged and elongated mitral leaflets contribute to left ventricular outflow tract obstruction and this phenomenon appeared predominantly in males. Such a group dominated by males (79%) had greater left ventricular end-diastolic dimension than patients with obstructive hypertrophic cardiomyopathy and normal-sized mitral valve [21]. Additionally, males predominated among patients with obstructive hypertrophic cardiomyopathy, in whom myotomy–myectomy was supplemented by plication of anterior mitral valve leaflet due to its elongation [23]. Accordingly, we hypothesised that similar mitral leaflet elongation may be frequent in our male patients and therefore the mechanism by which left ventricular outflow tract gradient is induced may be different in each gender. We were unable to confirm this hypothesis, because gold standard, i.e. mitral valve specimens [21,22], were unavailable in our study and the technical quality of images from transthoracic echocardiography was not sufficient in a substantial portion of our patients to reliably measure mitral leaflet parameters. Similar to us, mitral valve dimension was also difficult to reliably assess by transthoracic echocardiography in previous studies [21,22] and therefore intraoperative epicardial echocardiography was used

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in about one third of study patients to obtain optimal image quality.

4.1. 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 next limitation is inability to precisely measure mitral leaflets by transthoracic echocardiography in all our patients. Transthoracic echocardiography was an adequate method to assess mitral valve only in highly-selected patients [22]. Transoesophageal echocardiography seems to be of sufficient technical quality to assess quantitatively mitral valve apparatus [24,25] Thus, the prospective transoesophageal echocardiography with mitral valve measurements supplementing our retrospective analysis is required to elucidate the potential gender-specific difference in the mechanism of left ventricular outflow tract gradient induction. The transoesophageal echocardiographic approach [25] should allow to precisely determine the mitral leaflets elongation and thickness as well as distance between papillary muscle and anterior mitral annulus. In conclusion, females with hypertrophic cardiomyopathy featured smaller left ventricular cavity size, which predisposed to left ventricular outflow tract obstruction. The most potent predictor of left ventricular outflow tract obstruction was left ventricular end-systolic dimension. Also higher left ventricular contractility, however with less statistical power, determined left ventricular outflow tract gradient occurrence in hypertrophic cardiomyopathy females. In males, despite a larger left ventricular cavity size, the left ventricular outflow tract obstruction appeared with similar frequency as in females. Left ventricular outflow tract obstruction was not predicted by left ventricular cavity size or contractility in males. In patients with hypertrophic cardiomyopathy the small left ventricular cavity size and left ventricular outflow tract gradient are risk factors of sudden death

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[1–3]. Therefore, the smaller left ventricular cavity predisposing to left ventricular outflow tract gradient in females requires further evaluation (in a larger population) in respect to potentially increased risk of sudden death in hypertrophic cardiomyopathy females in comparison to males.

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