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Cardiovascular Research 2001 49(2):340-350; doi:10.1016/S0008-6363(00)00280-7
© 2001 by European Society of Cardiology
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Copyright © 2000, European Society of Cardiology

Gender-related differences in left ventricular chamber function

Christopher S Haywarda,b,*, Wally V Kalninsa and Raymond P Kellya

aDepartment of Cardiology, St Vincent's Hospital, Victoria St, Darlinghurst, NSW 2010, Australia
bDepartment of Cardiac Medicine, NHLI, Imperial College, London, UK

* Corresponding author. Tel.: +61-2-8382-6880; fax: +61-2-8382-6881 chayward{at}stvincents.com.au

Received 5 April 2000; accepted 18 October 2000


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objectives: While women have lower rates of atherosclerotic disease than men, they are more likely to suffer cardiac failure following infarction or cardiac surgery, despite typically having a greater left ventricular (LV) ejection fraction. We hypothesised that gender differences in systolic chamber function and ventriculo-vascular coupling may contribute to these clinical findings. Methods: LV chamber function was determined in a cohort of 30 patients (16 women) aged 48–75 years with normal LV function using pressure-volume loops obtained by simultaneous conductance catheter volumetry and micromanometer pressure. End-systolic and end-diastolic pressure volume (ESPVR, EDPVR) and preload recruitable stroke work relations (PRSWR) were derived. Results were analysed according to gender, and the effects of body size and chamber dimensions were examined. Results: The groups were closely matched for age (60±6 vs. 60±8 years) and co-morbid conditions. Women had higher end-systolic blood pressure (139.7±21.1 vs. 123.6±12.6 mmHg, P = 0.001), and smaller LV cavity volume (end-diastolic volume 96.4±30.6 vs. 139±30.7 ml, P = 0.001). Women had significantly higher LV end-systolic elastance (Ees, 2.65±0.10 vs. 1.96±0.09 mmHg ml–1, P<0.002), arterial elastance (2.41±1.13 vs. 1.54±0.55 mmHg ml–1, P = 0.01) and lower passive LV diastolic compliance (slope EDPVR, 6.12±0.37 vs. 10.0±0.50 ml mmHg–1, P<0.001). While there was a strong relationship between end-systolic elastance and chamber volume (r = 0.69, P<0.001), gender differences in chamber function all persisted after indexing to body size. Higher LV systolic function in women was also shown in PRSWR analysis (slope, MSW; 101.4±3.8 vs. 90.4±2.8 mmHg, P<0.05), which is independent of chamber size. After normalising volumes to resting diastolic volume, the greater systolic and diastolic elastance in women was accounted for. The ratio of end-systolic to arterial elastance, a measure of ventriculo-vascular coupling, was similar in women and men (1.19±0.40 vs. 1.54±0.30, respectively, P = 0.23). Conclusions: This study demonstrates greater systolic chamber function and lower diastolic compliance in women. Within the range of chamber dimensions seen in patients with normal LV function, a strong relationship was found between cardiac size and end-systolic elastance. While these differences were not accounted for by indexing to body size, the greater ventricular elastance in women was removed after normalising to chamber size. Despite differences in resting ventricular elastance, appropriate ventriculo-vascular coupling was maintained in both genders as the greater end-systolic elastance in women was matched by similarly elevated arterial elastance.

KEYWORDS ESPVR, end-systolic pressure-volume relationship; Ees, end-systolic elastance; P0, pressure at zero volume; V0, volume at zero pressure; V100, volume at 100 mmHg; EDPVR, end-systolic pressure-volume relationship; Eed, end-diastolic elastance; CDia, diastolic compliance; PRSWR, preload recruitable stroke work relationship; MSW, slope of PRSWR; SW0, stroke work at zero volume; V0SW, volume at zero stroke work; V7500, volume at 7500 mmHg ml–1


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
Gender differences in left ventricular (LV) chamber function are suggested by clinical studies which have found higher rates of cardiac failure in women despite higher ejection fractions than men post myocardial infarction [1,2], a higher prevalence of diastolic heart failure in women [3], and higher rates of myocardial rupture compared to men following myocardial infarction [4]. Furthermore, women tend to develop greater hypertrophy and have more maintained ventricular function in response to hypertension [5] or aortic stenosis [6] compared to men. Even in the absence of cardiovascular disease, a number of studies have shown women to have higher LV ejection fraction and fractional shortening compared to men [7,8]. While these latter two indices are load dependent, they are independent of chamber size, suggesting a true gender-specific difference.

In view of this, intrinsic differences in cardiac mechanics need to be considered. There has been no prior examination of the influence of gender on load-independent indices of LV chamber performance in humans. We hypothesised that some of the gender differences in clinical findings may be an expression of differences in systolic and diastolic chamber function. This study therefore examined LV pressure-volume relations in a cohort of men and women undergoing cardiac catheterisation. We further examined whether the differences seen may be attributed to gender-related differences in body size or LV chamber dimensions.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
2.1 Patient population
The study was approved by the Research and Ethics Committee of St Vincent's Hospital, Sydney, Australia, and all patients gave written informed consent. The investigation conforms to the principles outlined in the Declaration of Helsinki. A total of 30 subjects (16 women, 14 men) with normal LV function and no history of myocardial infarction or clinical heart failure were recruited from patients undergoing routine cardiac catheterisation. Demographic data, including age, were well matched between men and women (Table 1). All women studied were clinically post-menopausal (defined by a minimum of 12 months amenorrhea). Distribution of co-morbidity (diabetes, hypercholesterolaemia, smoking) was similar. Women did have a slightly higher rate of hypertension (10/16) compared to men (5/14) as is found in the general population after age 55 years [9] though this again was not significantly different between groups (P = 0.27). Medications were continued until morning of study. Most subjects were receiving anti-anginal therapy at the time of cardiac catheterisation. There were no significant differences in the spectrum of medications taken by either gender. All patients had normal LV function and no segmental abnormality on contrast ventriculography. No patient had aortic or mitral valve disease. The range and severity of coronary artery disease was well matched (Table 1). A total of seven men and ten women had no significant angiographic disease, while four men and four women had triple vessel coronary disease. All patients were in sinus rhythm apart from one subject who had intermittent ventricular trigeminy.


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  		Table 1 Baseline demographics of gender study population

 
Differences in body size were accounted for using either height or body surface area (BSA) calculated according to BSA=m0.75xht0.45x71.84 where m is mass (kg), ht is height (cm) and BSA is in cm2 [10]. As expected, women were shorter, lighter and smaller with significantly smaller body surface area (Table 1).

2.2 Data acquisition
Left ventricular pressure-volume (PV) loops were obtained by simultaneous measurement of LV pressure (micromanometer) and volume (conductance method) as has been previously described [11,12]. Briefly, an 8F-conductance volume catheter (9-mm electrode spacing, Webster 7212-08, Webster Laboratories) was inserted into the LV cavity under fluoroscopic control. The micromanometer was then inserted to the tip of the volume catheter. Volume signals were processed via a Leycom signal conditioner (Sigma 5, Cardiodynamics, Rijnsburg, The Netherlands) to a data acquisition board in a portable computer (Intel 486 processor, DX50) and displayed on-line at a sampling rate of 250 Hz with high frequency noise filtering cut-off at 50 Hz, 20dB/decade. End-systolic and end-diastolic volumes (ESV, EDV) were calculated off-line using single-plane contrast ventriculography, calibrated against a radio-opaque sphere of known diameter. A 35-mm vena caval balloon catheter (Cordis 530000A-15565, Cordis, Miami, FL) positioned within the right atrium was used for acute preload reduction by intermittent inferior vena caval occlusion (IVCO). Inferior vena caval occlusion was achieved by brief inflation of vena caval balloon with 30–35 ml of carbon dioxide in the right atrium (for 8–10 s or until ventricular ectopy occurred), and then gently withdrawing the catheter to lodge in the mouth of the inferior vena cava. In some patients, IVCO remained unsuccessful, due to frequent ventricular ectopy induced by reduction of the ventricular volume around the volume catheter.

2.3 Data analysis — steady state data
Data sets in a stable rhythm were collected for ‘steady-state’ analysis. Steady-state data for each patient were averaged over ten to 20 continuous beats. Data in which there was a >10% change in heart rate were excluded. Pre-ectopic, ectopic and post-ectopic beats were excluded from analysis. Steady-state parameters were automatically determined from the averaged PV loop by customised software (PVAN, Pressure-Volume Analysis, Johns Hopkins University, Baltimore, MD). Steady-state variables included heart rate, cardiac output, LV systolic pressure, end-diastolic pressure (pre a-wave), peak positive dP/dt (dP/dtmax), peak negative dP/dt (dP/dtmin), time constant of relaxation (T, {tau}), duration of contraction and end-systolic pressures and volumes. End-diastolic parameters were measured immediately prior to the atrial filling wave. End systole was defined by the maximum of time varying ventricular elastance (Et) as described by the equation Et = Pt/(Vt–V0), where V0 is the volume axis intercept as described below. {tau} was determined using a logarithmic least-squares regression commencing at peak relaxation (dP/dtmin) and extending for a further 80 ms. Duration of electromechanical systole (duration of contraction) was defined from the midpoint of the electrocardiographic QR wave to dP/dtmin [13].

2.4 Data analysis — chamber function
The load-independent indices end-systolic PV relations (ESPVR), preload-recruitable stroke work relations (PRSWR) and end-diastolic PV relations (EDPVR) were obtained during transient IVCO. As linear relationships were assumed for all indices, individual IVCO runs with a linear correlation of less than 0.8 were excluded. An iterative procedure was performed from the linear regression of the lines using an initial estimate of V0 of 0 ml. Subsequent iterations were continued until errors were minimised as previously described [11,14]. Due to poor correlations in individual runs or ventricular ectopy in response to IVC occlusion, some studies were found to be unsuitable for load-independent analyses. The average (±S.D.) of the individual correlations for ESPVR for the studies included was 0.90±0.06.

End-diastolic relationships were determined from two EDP/EDV points on each PV loop. The points chosen were those immediately prior to the a-wave and a second point 10% of the filling volume earlier in the same loop as has been described previously [15]. By examining diastole prior to atrial contraction, this provides an assessment of the passive diastolic properties of the left ventricle. A linear model was used to describe the EDPVR as this is simpler and has been shown to be as valid as more complex exponential regression models [16]. Although the slope of the regression describes an elastance, the results are usually reported as the inverse, namely chamber compliance, CDia [17]. The equation for diastolic compliance is therefore V = CDia·P+V0Dia, where V0Dia is the volume axis intercept.

2.5 Data analysis — averaging of pressure-volume loops
Because visual display of PV loops allows rapid assessment of the cardiac cycle, we developed a new averaging method for data presentation. Representative PV loops for each individual were obtained by averaging up to 20 steady-state loops for each subject (Fig. 1). As the heart rate did not vary significantly, this was achieved by averaging the pressure and volume independently. When averaging across the population, where heart rates were significantly different, the loops were interpolated to generate 200 data points for the duration of systole. Onset of systole was defined as the time at which dP/dt reached 50% of its maximum. Duration of systole was defined from onset of contraction to the time of maximal ventricular elastance [18]. This normalisation for systole allowed loops from each subject to be ensemble-averaged to create an overall average for each gender group. As varying heart rates and the normalisation process led to PV loop files with different number of data points, the average loop for each gender was then truncated to the shortest file. To display estimates of error (standard error of the mean, S.E.M.), a novel elliptical display program was written using AXUM Scientific Software (AXUM 5.0A, MathSoft). The S.E.M. for pressure was calculated for every point and is displayed as the short axis of the ellipse for each point. S.E.M. for volume is shown as the long axis of the ellipse for each point.


Figure 1
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  		Fig. 1 An example of calculation of averaged pressure-volume loops for two individuals. Raw loops are shown as light lines with the calculated average in bold.

 
2.6 Statistics
Results for steady-state haemodynamic parameters are shown as mean±S.D., and were compared using unpaired t-tests. Significance of differences in categorical variables was determined using Fisher's exact test. Significance of multiple comparisons was determined using a one-way analysis of variance with post hoc comparisons made using the Student–Newman–Keuls test (Primer of Biostatistics 4.0, McGraw Hill). Results for ESPVR, EDPVR, and PRSWR were calculated using multiple linear regression analysis with complete coding for individual differences in slope and offset [19], and are presented as mean coefficient for each gender±standard error of the estimate (S.E.E.) (SPSS for Windows 6.1, SPSS). Pressure was used as the dependent variable in all regressions involving ESPVR and EDPVR and stroke work was used as the dependent variable for PRSWR. One female subject was excluded from ventricular volume analyses and calculations due to difficulties with ventricular volume measurements. Significance was set at P<0.05.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
3.1 Steady state
Gender differences in steady-state parameters are summarised in Fig. 2a and Table 2. Women had significantly higher resting heart rates and peak and end-systolic pressures. End-diastolic pressure (pre a-wave) was not significantly different between men and women. As expected, women had significantly smaller hearts with significantly smaller end-diastolic and end-systolic volumes (Table 2). Stroke volume was also smaller, but in combination with a higher resting heart rate, cardiac output was similar in men and women. These differences can be rapidly appreciated in the ensemble-averaged PV loops for each gender (Fig. 2). The systolic portion of the loop in women is more peaked compared to a relatively flat systolic portion in the males. The diastolic portion of the steady-state loops is very similar. Pressure-dependent indices of systolic and diastolic function, and duration of contraction were similar between men and women. Despite the higher systolic pressure generated in women, LV stroke work was similar between the genders, due to smaller stroke volumes in women.


Figure 2
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  		Fig. 2 (A) Ensemble-averaged PV loops with ellipse representing±S.E.M. for both pressure and volume. Women have smaller volumes and higher systolic pressures. The average arterial elastance for men and women is shown diagrammatically (women, light line; men, solid line). (B) Ensemble-averaged pressure-volume loops after indexing to body surface area loops for each gender. Gender differences in volumes were decreased by indexing (B). Women light line, men solid line, with the average for both in bold. See text for description of the method of averaging.

 

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  		Table 2 Effect of gender on steady state haemodynamics

 
3.2 Gender differences in steady-state haemodynamics in the absence of hypertension
While the frequency of hypertension was not significantly different between the two groups, it may still have contributed to the gender differences found. Analysis of normotensive subjects (six women and nine men) showed that the gender differences were greatly diminished (Table 3). There were no significant gender differences in steady state haemodynamics, albeit in this subset of the study population.


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  		Table 3 Effect of gender on steady state haemodynamics in the normotensive subgroup

 
3.3 Effect of indexing to body surface area on gender differences in steady state haemodynamics
After indexing to body surface area, gender differences in LV volumes were reduced (Table 2, Fig. 2b). There remained an apparent gender difference in arterial elastance (with women having higher arterial elastance index), even after accounting for body surface area. This is despite the fact that body surface area normalised the gender difference in stroke volume, and relates to the higher end-systolic pressure in this group of women as well as the higher resting heart rate. There was no change in the significance of differences if indexing to body height, rather than body surface area, was used. While cardiac size, as defined by EDV, was significantly correlated with body surface area (r = 0.54, P<0.005), it only accounted for 29% of the variance in EDV.

3.4 Systolic LV chamber function — ESPVR and PRSWR
Results for those subjects in whom successful loading manipulation was performed are shown in Table 4. Of that cohort, four men and four women had coronary artery disease. A total of eight women (three with coincident diabetes) and two men were hypertensive. Women were found to have higher chamber performance for both ESPVR and PRSWR. This means that the pressure or stroke work generated for a given change in preload is greater in this group of women. These results are independent of the different resting blood pressures as they are measured across a range of pressures and volumes during IVCO. For both ESPVR and PRSWR, volume at operating pressure (at 100 mmHg, V100) and stroke work (at 7500 mmHg ml–1, V7500) are also reported. Consistent with larger resting cardiac volumes, men have higher operating volumes.


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  		Table 4 Effect of gender on chamber haemodynamicsa

 
3.5 Passive diastolic function — EDVPR
Despite men and women having similar resting end-diastolic pressures, women had lower LV passive diastolic compliance (Table 4). This suggests that a higher pressure is required to increase diastolic volume in women. Women also had a significantly, though not substantially, higher pressure offset (P0), of the order of 1.2 mmHg (0.8–(–0.4 mmHg)).

3.6 Effect of body and cardiac size on measures of ventricular function
To determine whether stature was predictably associated with indices of chamber function, scatterplots for individual's end-systolic elastance and height or BSA were derived. There was no relation between end-systolic elastance and body size (defined either by height or BSA, P = 0.76 and P = 0.10, respectively). However, there was a strong relation between elastance and the resting cardiac size (defined by resting end-diastolic volume, r = 0.64, P<0.005). The linear regression equation for the Ees–EDV relationship was Ees=5.0 (0.8)–0.022 (0.006)xEDV, P<0.005 (coefficient±S.E.E.). It can be seen that women are positioned in the upper left region of the graph, tending to have smaller resting cardiac volumes as well as higher end-systolic elastance (Fig. 3a). This relation was further examined according to allometric principles in log-linear relations [20]. The allometric correlation (loge(Ees) vs. EDV) was slightly stronger than the linear relation (P = 0.001, r = 0.69), with the log-linear equation loge(Ees)=1.89 (0.32)–0.01 (0.003)xEDV.


Figure 3
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  		Fig. 3 Relationship between cardiac size and end-systolic elastance (Ees). (A) There was a strong relationship between resting cardiac size as described by end-diastolic volume (EDV) and Ees. Women tend to be positioned in the upper left region of the graph, having smaller resting cardiac volumes and higher end-systolic elastance. (B) Once end-systolic volume was normalised to resting EDV (Ees'EDV), the size dependence of the relation was removed. F, females; M, males. Regression equation bold line; 95% confidence intervals, light line. Regression equation, correlation coefficient shown.

 
Indexing of ESPVR and EDPVR to body surface area (EesBSA and CDia BSA), as has been used previously [21,22], did not remove gender differences: EesBSA=4.24 (0.17) for women versus 3.76 (0.18) for men, (mmHg ml–1 m2, P<0.05) and CDia BSA=3.75 (0.24) for women versus 4.82 (0.24) for men (ml mmHg–1 m2, P<0.005). Because both elastance and compliance correlated better with resting EDV than BSA, the analysis was repeated using volumes indexed to resting EDV to calculate a normalised ESPVR' (Ees'EDV) and EDPVR' (CDia'EDV), respectively (Table 4). As can be seen from Fig. 3b the size dependence of this relation is removed and the greater female elastance is accounted for. The greater Ees'EDV in men (Table 4) may have been influenced by a significant outlier (above 95% confidence intervals; Fig. 3b) in this analysis. Because PRSWR uses the ratio of stroke work (the product of pressure and volume) to end-diastolic volume, it is unaffected by indexing volume. The higher chamber function suggested by PRSWR is therefore not dependent on the documented differences in body size, but because it is an integrated parameter throughout the cardiac cycle, it may be influenced by factors other than the end-systolic elastance.

3.7 Ventriculo-vascular coupling
Effective arterial elastance, calculated from the ratio of end-systolic pressure to stroke volume and representing a composite measure of arterial resistance and capacitance [23], was significantly higher in women (Table 2). In Fig. 2, an estimate of the average arterial elastance for men and women is shown as a light line for women and a bold line for men. The slope of the two ratios is obviously different. The ratio of ventricular end-systolic to arterial elastance, a measure of ventriculo-vascular coupling, was similar in women and men (1.19±0.40 vs. 1.54±0.30, respectively; P = 0.23). As a ratio, this is independent of differences in body size.


   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
This is the first study to examine gender differences in LV chamber function using pressure-volume analysis. Using the traditional load-independent indices of contraction, women in this study had higher chamber performance according to both end-systolic PV relations and preload recruitable stroke work relations. Women also had lower diastolic compliance compared to men. While a strong dependence of ventricular elastance on ventricular size was shown in this study, the gender differences in elastance are important in understanding responses to alterations in loading conditions associated with changes in fluid status or vascular tone. While PRSWR is a size-independent index of LV chamber systolic function [24], the gender differences were not as prominent as for either end-systolic or end-diastolic elastance.

4.1 Other studies of gender and ventricular function
Previous studies, using load-dependent indices of ventricular function have also suggested higher systolic function in women. Ejection fraction has been shown to be higher in women compared to men in a study of patients with normal coronary arteries at cardiac catheterisation [7], as has fractional shortening in a normotensive population [8]. A non-invasive study examining LV mid-wall shortening corrected for circumferential end-systolic stress has also found enhanced chamber function in both normotensive and hypertensive women compared to corresponding men [25]. In our study, while the ejection fraction was higher in women, it did not achieve statistical significance. Cardiac output was similar between men and women in the current study. This apparent similarity may have resulted from the small cohort size as previous studies have shown greater cardiac output in men related to their greater body size [26]. A higher resting heart rate in females has also been found in non-invasive studies and is consistent across all ages [27]. The faster heart rate in this study was not dependent on negative chronotropic agents as 12/14 men and 14/16 women were taking either β-blockers or calcium antagonists.

Gender differences in ventricular remodelling have been previously described with women typically having greater hypertrophy and more maintained LV function compared to men in response to both hypertension [5] and aortic stenosis [6]. The higher resting systolic chamber function in this study is consistent with such studies and may be a factor in the maintained systolic function seen in women under these conditions. The higher ventricular elastance seen in this study may not be without cost and may be significant in understanding the significantly higher rates of cardiac rupture following myocardial infarction seen in women [4].

There have been few gender comparisons of diastolic function, possibly due to the difficulty in defining this non-invasively. In the Framingham Study, transmitral flow velocity ratios were similar between men and women [28], though these are known to be exquisitely sensitive to loading conditions. One study did find lower absolute peak velocities in middle aged women, which may be consistent with diastolic dysfunction [29]. The presence of diastolic dysfunction with associated symptoms of congestive cardiac failure has been suggested as a factor explaining the higher ejection fraction in women in major heart failure trials [30]. The higher rates of clinical heart failure following myocardial infarction and bypass surgery [1,2] are also consistent with the findings of lower diastolic compliance, despite greater chamber function, from the current study. While left ventricular hypertrophy is associated with diastolic dysfunction, LV wall thickness was not measured in this study.

The gender-related differences in systolic chamber function found in this study are consistent with animal studies, which have also found enhanced systolic function in females compared to similar aged males. Studies have found that papillary muscles from female rats have greater rates of shortening compared to male rats [31], and across a range of calcium concentrations generate more tension per unit mass than male rats [32]. These differences have been attributed to differences in excitation–contraction coupling, and may further relate to different activity of cardiac actinomyosin ATPase [33]. One study, which found lower stroke work per unit mass in female rat hearts, was complicated by significant differences in the age of the rats studied [34].

4.2 Body size and ventricular function
With respect to resting cardiac volumes, we found that indexing to body size failed to account for gender-related differences in cardiac volumes. A previous study has found that simple indexing to BSA may be inadequate and suggested a non-integer exponent of body surface area as a correction factor [26]. Applying this regression to our data (SV=35.38xBSA1.19) did remove gender differences in stroke volume (1.04±0.30 vs. 1.15±0.40, P = 0.37), supporting those earlier results.

Left ventricular size has important effects on LV chamber function. As has been suggested previously, smaller LV chambers are associated with higher systolic elastance [35]. Attempts to correct for this have included normalising to body surface area [21,22], body weight or LV weight [36]. While normalising to body surface area has not been generally accepted [37], no appropriate alternative is agreed [38]. This study supports the contention that indexing to body surface area inadequately accounts for size related differences in chamber elastance and suggests that normalising to the individual's resting chamber volume (EDV) may be a better alternative. PRSWR, which are size-independent [16], were different between the gender groups in this study. The difference in MSW, however, was relatively smaller that the differences in elastance. It remains to be determined whether there is a structure (size)-related benefit in terms of systolic function due to the smaller LV cavity seen in women.

4.3 Arterial elastance and ventriculo-vascular coupling
This study found significantly higher arterial elastance in women compared to men, even after indexing to BSA, suggesting a gender-specific effect. The higher arterial elastance in women in this study confirms a previous report defined non-invasively using echocardiography and arterial tonometry, again independent of body size [39]. The differences in elastance in that study were correlated with differences in late systolic central pressure waveform augmentation. We have previously described higher late systolic augmentation of the central arterial pressure waveform in women compared to men consistent with this, incompletely explained by differences in stature [27]. Because arterial elastance is calculated using stroke volume it is dependent on ventricular size, in a similar fashion to ventricular elastance. A further non-invasive study also found lower arterial capacitance in women, but those differences were related to differences in body size [40]. These studies, using different techniques to define arterial function, are consistent with elevated pulsatile vascular afterload in women. The role of stature is incompletely defined.

In the current study, we have shown that the elevated arterial elastance in women is matched by higher ventricular (end-systolic) elastance suggesting maintenance of appropriate ventriculo-vascular coupling, despite the increased vascular load in women demonstrated by the above studies. One consequence of elevated ventricular and arterial elastance may be an increased sensitivity to fluid shifts. This has previously been described in relation to ageing to account for the higher frequency of hypotensive episodes in the older population [41]. A particular group of patients sensitive to fluid shifts are those with hypertensive hypertrophic cardiomyopathy [42]. This group is predominantly female and is characterised by recurrent episodes of pulmonary oedema despite supranormal indices of systolic ventricular function. The elevated ventricular and arterial elastance may also contribute to the greater hypertrophy that is seen in women in the presence of hypertension [5] or aortic stenosis [6].

4.4 Effect of hypertension on gender differences in haemodynamics
The greater frequency of hypertension in women in this study reflects the higher prevalence of hypertension in women in this age group of the Australian population [9]. While the frequency of hypertension was not significantly different between the two groups, it may still have contributed to the gender differences in haemodynamics found. Analysis of the subset of normotensive subjects in this study (Table 3) suggests that some of the gender differences in the entire cohort may have been related to the presence of hypertension. The higher systolic chamber function and lower diastolic compliance in the group of women in this study may also be related to the combination of diabetes and hypertension in the group. The pragmatic inclusion of hypertensives does make interpretation of gender differences more difficult, but it is this particular group that forms the patients seen in clinical practice, and clinically, this group is the more important to understand. Gender differences in expression of hypertension on ventricular chamber function need to be further addressed in larger groups of subjects.

4.5 Limitations
Because these studies are necessarily invasive, only those subjects undergoing planned cardiac catheterisation were enrolled. At present these indices are not reliably available non-invasively. While much of the difference in cardiac morbidity between men and women has been attributed to the difference in co-existing diseases or age [43], in this study the two groups were relatively well matched. While indices of chamber function have been shown to increase with age [41], we did not find any consistent age-effect, most likely related to the relatively narrow range studied.

Another limitation is the presence of coronary disease in some of the subjects. Absence of previous myocardial injury was defined historically as well as by normal LV ejection fraction and segmental motion on contrast ventriculography. Because these studies were undertaken at rest, the effect of any coronary stenoses on global ventricular function is likely to have been small. Sub-analyses revealed that systolic function was higher in women compared to men both in the presence of coronary disease as well as in its absence, though the results were not significant due to small numbers in each group. As all diabetic women were also hypertensive, a separate role for diabetes cannot be examined from this patient group. Larger studies, possibly using non-invasive techniques, are required to investigate the interaction of both hypertension and coronary artery disease as well as other risk factors with gender on LV chamber haemodynamics.

4.6 Conclusions
We found that, in this cohort, women have higher LV systolic chamber function and lower diastolic compliance compared to similar aged men. This difference remained after indexing LV volumes to body size, but differences in elastance were removed after accounting for resting diastolic volumes. Arterial elastance was also significantly higher in women than men but was matched with ventricular elastance resulting in appropriate ventriculo-vascular matching in both sexes. This study also demonstrates that LV chamber size is strongly associated with measurements of end-systolic elastance within the range of normal LV volumes suggesting that this, as well as gender, should be taken into account when reporting series of patients or analysing drug effects from different patient groups. Further studies are needed in subjects without co-morbidities such as diabetes and hypertension to further define the effect of gender on cardiac function. The greater end-systolic elastance and lower diastolic compliance in women described in this study may be relevant in understanding gender differences in rates of cardiac rupture and failure following myocardial infarction as well as greater loading sensitivity in women despite normal ejection fractions.

Time for primary review 22 days.


   Acknowledgements
 
The assistance of staff of the St Vincent's Hospital Cardiac Catheterisation Laboratory is gratefully acknowledged. This work was supported by a Postgraduate Research Fellowship for Dr Hayward, and a Project Grant for Dr Kelly, both from the National Health and Medical Research Council of Australia. Dr Hayward is currently supported by an Overseas Research Fellowship from the National Heart Foundation of Australia.


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

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