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(Chest. 2000;117:1094-1099.)
© 2000 American College of Chest Physicians

Sex Differences in Left Ventricular Geometry in Aortic Stenosis*

Impact on Outcome

Donna L. Milavetz, MD; Sharonne N. Hayes, MD; Susan A. Weston, MS; James B. Seward, MD; Charles J. Mullany, MB, MS and Véronique L. Roger, MD, MPH

* From the Division of Cardiovascular Diseases and Internal Medicine (Drs. Milavetz, Hayes, Seward, and Roger), the Section of Biostatistics (Ms. Weston), and the Division of Thoracic and Cardiovascular Surgery (Dr. Mullaney), Mayo Clinic and Mayo Foundation, Rochester, MN.

Correspondence to: Veronique L. Roger, MD, MPH, Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Summary
 References
 
Objective: This study of surgical aortic stenosis characterized sex differences in left ventricular (LV) geometry and outcome.

Materials and methods: We examined 92 women and 82 men who underwent echocardiography before valve replacement for aortic stenosis.

Results: Women had a smaller cavity size (LV end-diastolic diameter 48.2 ± 7 mm in women vs 53.6 ± 7.6 mm in men; p = 0.0001) and higher ejection fraction (59% in women vs 54% in men; p = 0.02). LV mass was greater in men than women (300.4 ± 88 g in men vs 250.6 ± 85.8g in women; p = 0.0055) but when corrected for body surface area, the difference was not significant. The prevalence of LV hypertrophy was similar in both sexes (51% in women vs 49% in men; p = 0.62). The 5-year survival was 82% in women and 79% in men (p = 0.9).

Conclusion: Several descriptors of LV geometry differed between men and women. These differences were largely eliminated after normalizing for body surface area. No differences in surgical mortality or long-term outcome were noted.

Key Words: aortic valve disease • outcome left ventricular geometry • sex difference


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Summary
 References
 
Several studies have emphasized the existence of sex differences in the left ventricular (LV) adaptation to aortic stenosis (AS).1 2 3 Supernormal LV function, a smaller LV chamber size, and thicker walls have been observed more frequently in women with AS. Sex differences in LV structure and adaptation to exercise paralleling such differences in LV geometry have also been documented.4 5 Controversy remains, however, on the impact of such sex differences on outcome. In some series,6 this pattern of LV geometry has been associated with increased surgical mortality in women, whereas other series failed to identify sex as an independent predictor of adverse outcome after valve replacement.7 8 9 The published studies are heterogeneous with regard to the prevalence of coronary disease and the overall operative mortality reported. This issue, therefore, needs to be examined in a larger series of patients with isolated AS.

The present study was designed to examine clinically used indicators of LV geometry in a large series of men and women with surgical AS and to test the hypothesis that there was no sex association in LV geometry and outcome after valve replacement in AS.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Summary
 References
 
All patients undergoing aortic valve replacement for AS between 1990 and 1992 were considered for inclusion in the study. Patients were included if they met the following criteria: age > 20 years at aortic valve replacement; absence of coronary artery disease as determined by preoperative coronary angiography (threshold of 50% for the significance of a stenosis); absence of concomitant valvular heart disease requiring surgical correction; and no more than mild aortic regurgitation, as determined by Doppler echocardiography.

The hemodynamic severity of AS and LV function were assessed by echocardiography with commercially available ultrasound systems. By using the American Society of Echocardiography measurement techniques, short-axis measurements of the LV end-diastolic (LVEDD) and end-systolic diameter (LVESD) were obtained, and the ejection fraction (EF) was calculated using the modified Quinones method whenever possible.10 The EF was visually estimated when no M-mode measurement could be obtained.10 11 Diastolic relative wall thickness was calculated as the ratio of twice the posterior wall thickness to LVEDD.12 13 On the basis of published data,6 we stratified patients by sex according to a relative wall thickness > 0.66 vs <= 0.66 to examine outcomes. LV mass was calculated from the M-mode measurements by the method of Devereux and Reichek.14 LV hypertrophy was defined using two different thresholds for the LV mass index: published values from the Mayo Clinic,15 > 132 g/m2 for women and > 144 g/m2 for men, and the criteria of Devereux et al,16 > 110 g/m2 for women and > 134 g/m2 for men.

Aortic valve area and mean gradient were assessed by two-dimensional and Doppler echocardiography with established techniques.17 18 The recording of the optimal transvalvular Doppler signal was ascertained by systematic recordings from all ultrasound windows. The aortic valve area was calculated using the continuity equation using the maximal transstenotic velocity recorded by continuous-wave Doppler; the velocity in the LV outflow tract recorded by pulsed-wave Doppler; and the LV outflow tract diameter measured from the parasternal long-axis view.17 18 Severe AS was defined as an aortic valve area < 0.7 cm2.

Overweight status was defined as a body mass index (BMI) >= 27.3 kg/m2 in women and >= 27.8 kg/m2 in men.19 The Charlson index,20 21 a validated summary method of classifying comorbidity to predict short- and long-term mortality from medical records, was used to measure the severity of comorbid illnesses.

Coronary angiography was performed in all patients as part of the preoperative evaluation.

Follow-Up
All participants in the study had provided prior approval for use of their medical records for research protocols. The protocol and follow-up survey were approved by our Institutional Review Board.

Postoperative morbidity (defined as sepsis, low cardiac output state, renal insufficiency requiring dialysis, permanent pacemaker implantation, inotropic support > 3 days postoperatively, ventricular arrhythmia requiring therapy, encephalopathy or neurologic disorder, and bleeding requiring reoperation) and mortality (within 30 days or same hospital stay) were examined through detailed review of the medical records. Long-term outcome was evaluated by a follow-up questionnaire designed by our Survey Research Center, focusing on the functional status of the patient. Nonresponders received a follow-up phone interview. Death certificates were obtained for all patients who died after hospital discharge. Late-outcome deaths occurring after hospital discharge were categorized as cardiac if attributable to myocardial infarction or congestive heart failure or if death occurred suddenly and unexpectedly. All other deaths during the follow-up period were defined as noncardiac.

Statistical Analysis
The data are presented in the text and tables as mean ± SD for normally distributed variables or medians and interquartile ranges in the case of nonnormal distributions (age, body surface area, and BMI). LV geometry was compared across the sexes using crude values, indexed values (divided by the body surface area), and adjusted values using multiple linear regression analysis to adjust for sex and body surface area. Comparisons of the baseline characteristics between men and women were performed using the two-sample t test or the Wilcoxon rank sum test for continuous variables and by the {chi}2 or Fisher’s Exact Test for categorical variables.

In comparing the effect of perioperative complications on perioperative survival, the Pearson {chi}2 test was used instead of survival analysis owing to the small number of deaths and the short follow-up time.

Kaplan-Meier curves were constructed to estimate survival after aortic valve replacement. Cox proportional hazards models were constructed to examine the association between several preoperative clinical and echocardiographic variables and death. Significance was judged at the level of p = 0.05.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Summary
 References
 
Baseline Characteristics
Two hundred thirteen patients underwent valve replacement during the study period. Thirty-two patients underwent coronary revascularization plus aortic valve replacement, and seven patients underwent other valve replacements in addition to the aortic valve. The remaining 174 patients met all entry criteria and are the subject of this study. Ninety-two (53%) were women and 82 were men. All but one female patient (99%) responded to the follow-up questionnaire sent in December 1994. One female patient’s information was missing at the time of the analysis. Demographic and baseline Doppler echocardiographic data are presented in Table 1 . At the echocardiographic study, women tended to be older than men but equally symptomatic. Women were smaller than men in terms of body surface area. Men had a higher median BMI than women, but there was no sex difference in the percent classified as overweight. The Charlson index was also similar for men and women.


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  		Table 1. Demographics and Clinical Characteristics at Time of Operation*

 
Hemodynamic Severity of AS and LV Systolic Function
Stenotic Indexes
The aortic valve area was smaller in women, but when corrected for body surface area, this difference was not significant. There was no sex difference in mean gradient.

LV Function and Geometry
There were significant differences in LV function between men and women despite a similar degree of AS (Table 2 ). In particular, EF and cardiac index were all higher in women.


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  		Table 2. Doppler Echocardiography Variables at Aortic Valve Replacement*

 
The LVEDD was larger in men, but after indexing the direction, the sex difference was reversed and the index value was larger in women. This was not observed with the use of regression analysis, where there was no sex difference in the adjusted LVEDD.

No sex differences were observed in the septal or posterior wall thickness between the two groups. LV mass was lower in women, but after indexing, the LV mass index was similar. Fifty-one percent of the women and 49% of men (p = 0.76) had LV hypertrophy using laboratory-based criteria. Using the criteria of Devereux et al,16 53% of the women and 49% of men had LV hypertrophy (not significant).

Twelve percent of women vs 8.5% of men had a relative wall thickness > 0.66 (p = 0.46).

Five patients had missing LVESD and 59 patients had missing LVESD and LVEDD. The analyses were repeated excluding the patients with missing diameters, and the results were unchanged.

Outcome
Mean follow-up was 1,269 ± 320 days. Seven patients died within 30 days or during the same hospital stay after aortic valve replacement. There was no sex difference in perioperative mortality (Table 3 ). A total of 19 late deaths were noted: 10 in women and 9 in men (p = 0.98). The causes of late death are listed in Table 3 .


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  		Table 3. Perioperative and Late Deaths According to Sex

 
At last follow-up, 89% of the women and 88% of the men were in New York Heart Association classes I and II.

There were no sex differences in Kaplan-Meier survival curve estimates (p = 0.9) (Fig 1 ). The 5-year Kaplan-Meier survival estimates were 82% for women and 79% for men.



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  		Figure 1. Kaplan-Meier survival curve indicates that 79% of men and 82% of women were alive after valve replacement for isolated AS. NS = not significant.

 
The following variables were included as candidate variables in multivariate models to identify predictors of survival: age, sex, EF, LV mass and mass index, and wall thickness-to-radius ratio. Only increasing age was significantly associated with poorer survival (p < 0.0018).

In the subgroup of patients with a relative wall thickness > 0.66, there was no sex-related difference in long-term mortality. Two of 11 women (18%) and one of seven men (14%) died (p = 0.8).


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Summary
 References
 
In the present series of men and women with isolated severe AS, significant differences in LV function and LV geometry were noted. The EF and cardiac index were higher in women, but the differences in LV geometry were mainly related to sex differences in body surface area. Indeed, after adjusting for body surface area, the only sex difference in LV geometry was a small but statistically significant increase in the LVEDD index in women. The cardiac index was higher in women, in keeping with the greater EF and LVEDD index. Operative mortality and long-term outcome after valve replacement did not differ according to sex.

LV Geometry
Several studies have indicated that women with severe AS are more likely than men to respond to the pressure load with concentric hypertrophy1 2 6 22 and hyperdynamic (supernormal) LV systolic function. Table 4 summarizes selected findings of some of these studies. The series differ in terms of design, number of patients, and prevalence of coronary artery disease. Not unexpectedly, they also differ with regard to the prevalence of sex differences in LV geometry.


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  		Table 4. Published Studies and Present Series: Sex Differences in LV Geometry Variables*

 
The studies by Carroll et al1 and by Douglas et al22 can be informally compared with the present series, because patients with coexisting coronary artery disease were excluded from all three series, which all pertained to patients with severe AS, with similar degrees of valvular obstruction, referred to cardiac catheterization, aortic valve replacement, or valvuloplasty. All three series reported supernormal systolic performance in women with higher fractional shortening, EF, and cardiac index.

Systolic and diastolic cavity dimensions were also uniformly smaller in women. Although there was no sex difference in wall thickness, LV mass was greater in men than in women. This is not unexpected because the calculation for LV mass incorporates the cavity dimensions, which are higher in men. The studies differ with regard to the existence of sex differences in indexed values. This may reflect differences in body habitus among the three studies. The use of indexed values to adjust echocardiographic dimensions remains controversial.23 Although we elected to present index values in the present study, when linear regression analysis was used, no sex difference in LVEDD was found in our series. This further underscores the limitation of controlling for body size by adjusting for body surface area.

The prevalence of LV hypertrophy using predefined as well as laboratory-specific criteria did not differ according to sex in the present study, which is at odds with the findings reported by Douglas et al.22 In that series, however, the population was older and had a greater prevalence of heart failure, which is likely to affect LV geometry and could conceivably confound some of the sex-specific findings. The lack of control for hypertension may also compromise the interpretation of these findings. In an exploratory analysis of the present series, excluding persons with a history of hypertension resulted in nonclinically significant changes of the sex differences in LVEDD, EF, and cardiac index. With regards to LV mass index, excluding patients with hypertension indicated a significantly lower LV mass index in women (130.7 ± 35.6 in women vs 151.7 ± 30.2 g/m2 in men; p = 0.043), adding more support toward the lack of an excessive degree of hypertrophy in women as compared with men. Although these results have to be interpreted with caution inasmuch as they were obtained from secondary analyses, survival analysis stratified by hypertension status did not unmask any sex difference in outcome. Thus, although there is some consistent evidence across published studies that LV function indexes in severe AS differ according to sex, some uncertainties remain with regard to sex-specific patterns of LV geometry (mass index, relative wall thickness, prevalence of LV hypertrophy) associated with severe AS in clinical practice.

Outcome
Regardless of their interpretation, the sex differences discussed above pose an important clinical question because some series have reported worse operative mortality for valve replacement in patients with concentric LV hypertrophy, small cavity size, and hyperdynamic LV systolic function.2 6 Inasmuch as these findings are more prevalent in women, they raise the concern of possible excess operative mortality among women with surgical AS. Yet there is little data on the outcome associated with the reported sex-differences in LV geometry.2 3 5 22

The outcome of the present population does not support this concern of an excess operative mortality among women inasmuch as no sex difference in postoperative or long-term outcome was noted. In contrast to other reports,8 9 our study represents a group of patients with isolated AS. Excluding coexisting coronary artery disease is important to assist in the interpretation of the outcomes, because its presence may adversely and independently affect outcome.2 6 Indeed, revascularization adds a small increase in the operative risk of aortic valve replacement, which could conceivably apply more to women.9 It has been suggested that because women are older at the time of revascularization, have smaller target vessels, and have more comorbid illnesses, this increases mortality rates from revascularization procedures compared with men.24 Finally, in some of these series, the operative mortality for valve replacement was 22%,6 which is higher than the reported average mortality for aortic valve replacement in other studies of 4.2 to 6.6%,9 25 26 27 28 raising the concern about selection bias and limited relevance to the general population.

The present series differs from previous reports in that it included a large number of consecutive patients who underwent aortic valve replacement for AS during the study period without associated coronary disease. The evaluation of patients with AS is routinely conducted using Doppler echocardiography,29 which protects from the selection biases outlined above and positively impacts the generalizability of our data. The operative mortality in the present series is similar to previously reported figures.

Limitations
This study was retrospective, and it is conceivable that some determinants of outcome were not captured at aortic valve replacement. In this surgically defined population, the decision made by the physician to refer the patient for aortic valve replacement may have been influenced by factors possibly confounding the association between sex or other variables and outcome.

Some determinants of LV geometry were not captured in our series. In particular, no measure of wall stress was obtained. However, all clinically used indexes of LV geometry were included. Although our study showed that women had a higher EF and a larger LVEDD index, and that > 50% of the women had LV hypertrophy, intracavitary flow acceleration was not routinely assessed. For consistency, we elected to use measurements similar to those used in previous studies; however, LV volume measurements are important in the analysis of LV geometry and should be the subject of future studies. Volumetric measures of the LV would have been desirable but were not performed routinely in our practice during the study period.

It has been suggested that a relative wall thickness >= 0.66 is associated with a trend toward increased mortality.6 No increased mortality was associated with a relative wall thickness >= 0.66 in our series, but the series may lack power for this analysis.


   Summary
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Summary
References
 
In this large clinical series of surgical AS, there were sex differences in LV geometry, but these differences were largely related to differences in body surface area. No sex difference in outcome was observed.


   Acknowledgements
 
The authors thank Sara L. Osborn Butler for help with data collection, Michelle Gayari for assistance with data analysis, and Paulette E. Schurhammer for excellent secretarial support.


   Footnotes
 
Abbreviations: AS = aortic stenosis; BMI = body mass index; EF = ejection fraction; LV = left ventricular; LVEDD = LV end-diastolic diameter; LVESD = LV end-systolic diameter

Received for publication April 15, 1999. Accepted for publication October 5, 1999.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Summary
 References
 

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