EXPERIMENTAL STUDIES
Hypertrophic remodeling: gender differences in the early response to left ventricular pressure overload
Pamela S. Douglas, MD, FACC*,
Sarah E. Katz, BA*,
Ellen O. Weinberg, PhD*,
Ming Hui Chen, MD*,
Sanford P. Bishop, PhD and
Beverly H. Lorell, MD, FACC*
* Cardiovascular Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA
Manuscript received March 3, 1998;
revised manuscript received June 2, 1998,
accepted June 12, 1998.
Address for Correspondence: Pamela S. Douglas, MD, Cardiovascular Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard-Thorndike Laboratory, 330 Brookline Avenue, Boston, MA 02215
pdouglas{at}bidmc.harvard.edu
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Abstract
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Objectives. To identify gender differences in left ventricular remodeling, hypertrophy, and function in response to pressure overload due to ascending aortic banding in rats.
Background. Gender may influence the adaptation to pressure overload, as women with aortic stenosis have greater degrees of left ventricular hypertrophy and better left ventricular function than men.
Methods. Fifty-two weanling rats underwent ascending aortic banding (16 males, 18 females), or sham surgery (9 males, 9 females). At 6 and 20 weeks, rats underwent transthoracic echo Doppler studies, and closed-chest left ventricular pressures with direct left ventricular puncture. Perfusion-fixed tissues from eight rats were examined morphometrically for myocyte cross-sectional area and percent collagen volume.
Results. At 6 weeks after aortic banding, left ventricular remodeling, extent of hypertrophy, and function appeared similar in male and female rats. At 20 weeks, male but not female rats showed an early transition to heart failure, with onset of cavity dilatation (left ventricular diameter = 155% vs. 121% of same-sex sham), loss of concentric remodeling (relative wall thickness = 102% vs. 139% of sham), elevated wall stress (systolic stress = 266% vs. 154% of sham), and diastolic dysfunction (deceleration of rapid filling = 251% vs. 190% of sham). Left ventricular systolic pressures were higher in female compared with male rats (186 ± 20 vs. 139 ± 13 mm Hg), while diastolic pressures tended to be lower (14 ± 4 vs. 17 ± 4 mm Hg).
Conclusions. Gender significantly influences the evolution of the early response to pressure overload, including the transition to heart failure in rats with aortic stenosis.
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Abbreviations and Acronyms
| | LV | = left ventricular | | LVH | = left ventricular hypertrophy |
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Left ventricular hypertrophy (LVH) is a compensatory process occurring in many forms of heart disease. Because of its importance, much attention has been focused on its determinants and modulators. Recently, gender has been proposed as an influence on hypertrophy, with female patients with aortic stenosis having increased hypertrophy, greater concentric remodeling, and better preservation of left ventricular (LV) function than male patients (1,2–6). While these differences have been attributed to gender, other influences cannot be excluded, including variations in the severity and duration of stenosis, concomitant coronary insufficiency, or even selection bias or gender differences in the care of patients with aortic stenosis. Further, while the process of hypertrophic remodeling, which occurs early in response to pressure overload, is of particular interest, this cannot be fully addressed in humans, as hypertrophy is usually only recognized clinically after achieving a steady state due to a chronic process. Studies of spontaneously hypertensive rats have shown less development of hypertrophy in females initially, followed by more extensive concentric remodeling and better preservation of LV function (7,8). However, this model does not successfully exclude genetic gender-related differences in neurohumoral or other growth factors, which may influence left ventricular geometry and mass (9–12). The ascending aortic stenosis model of pressure overload and LVH has been extensively characterized in our laboratory in male rats, including ventricular remodeling, hypertrophy, and in vivo function (13–20). Early, compensated hypertrophy with preserved systolic function progresses to decompensation with cavity dilation, and reduced contractile and diastolic performances (20). Accordingly, we sought to study gender influences on the development of hypertrophy in a model of pressure overload created by ascending aortic banding in weanling rats, which eliminates differences in age, duration, and degree of aortic stenosis, and other concomitant diseases.
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Methods
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Male and female weanling Wistar rats (body weight 60–70 g; age 3–4 weeks; Charles River Breeding Laboratory) were subjected to supravalvular aortic banding with a 0.58-mm internal diameter tantalum clip (16 males, 18 females), according to methods previously described by our laboratory (13–20). Additional animals underwent left thoracotomy without placement of the clip to serve as sham-operated age and gender-matched controls (9 males, 9 females). All animals were housed in a viral antigen-free facility and were fed normal rat chow (Purina) and water ad libitum. Animal studies were performed in accordance with institutional guidelines and approval.
At 6 and 20 weeks after aortic banding, rats were weighed, had tail cuff blood pressures measured, and underwent transthoracic echocardiographic/Doppler studies. Details of our methodology for performing transthoracic echo/Doppler studies in rats have been published, including their anatomic validation, and acceptable intraobserver (2.8%) and interobserver (6.3%) variabilities (20,21). Briefly, rats were lightly anesthetized with intraperitoneal ketamine HCl (50–75 mg/kg) and xylazine (10–15 mg/kg). Using a commercially available echocardiographic machine equipped with a 7.5-MHz transducer (Hewlett-Packard), a two-dimensional short axis view of the LV was obtained at the level of the papillary muscle. M-mode tracings of the anterior and posterior LV walls were recorded at a paper speed of 100 mm/s. Anterior and posterior wall thicknesses (at end-diastole and end-systole) and LV internal dimensions were measured using a modification of the American Society of Echocardiography leading edge method from at least three consecutive cardiac cycles on the M-mode tracings. The leading edge of the anterior wall is frequently difficult to identify, so the inner edge of this wall was used. The M-mode recordings were analyzed using a commercially available off-line analysis station (Tomtec) by a single observer blinded to animal groups. Representative M-mode echo tracings are shown in Figure 1.
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Figure 1 Examples of M-mode echocardiograms, trans-mitral Doppler flow signals, and LV pressure tracings in anesthetized rats 20 weeks after sham surgery (top), or aortic banding, LVH (bottom). There is increased LV wall thickness in the LVH rats, accompanied by a restrictive mitral filling profile. Note the very diminutive A-wave in the mitral inflow trace at similar heart rate to that seen in the sham animals. Both LV systolic and diastolic pressures are elevated in the LVH rats.
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LV mass was calculated using a standard cube formula, which assumes a spherical LV geometry according to the formula: LV mass = 1.04 x {[LVDd + PWT + AWT]3 – LVDd}, where 1.04 is the specific gravity of muscle, LVDd is LV end-diastolic dimension, PWT is diastolic posterior wall thickness, and AWT is diastolic anterior wall thickness. Because of underlying differences in body and heart size in male and female rats, data were normalized in two ways: by body weight, as in convention, and for LVH animals, as a percent of same-sex sham values. This latter normalization eliminates any possible confounding influence arising from underlying gender differences in values normalized to body size. Variables expressed as ratios, such as relative wall thickness, were not normalized to body weight.
We have previously demonstrated a good correlation between LV mass calculated in this manner and postmortem LV weight in rats (r = 0.78, standard error of the estimate = 0.124, p <0.0001) (15).
Endocardial shortening was calculated as: [(LVDd – LVDs)/LVDd] x 100, where LVD = LV internal dimension at end-diastole (d) and end-systole (s). In addition, since the inner half of the LV wall contributes more to total wall thickening in the outer half, we also calculated midwall shortening according to the two-shell cylindrical model of Shimizu et al. (22). This model does not require the assumption that a theoretical midwall circumferential fiber maintains its relative midwall position throughout the cardiac cycle.
Pulsed-wave Doppler spectra of mitral inflow were recorded from an apical four-chamber view, with the sample volume placed near the tips of the mitral leaflets and adjusted to the position where the velocity was maximal and the flow pattern was laminar. The sample volume was adjusted to the smallest size available (0.6 mm). The left atrium was then interrogated with pulsed-wave Doppler for the presence of mitral regurgitation. All Doppler spectra were recorded on paper at 100 mm/s and analyzed off-line as previously described. Measurements represent the mean of at least three consecutive cardiac cycles, and include peak early velocity, E; late velocity, A; their ratio, E/A; and the deceleration slope of rapid filling, E decel. Representative Doppler tracings are shown in Figure 1.
Hemodynamic studies.
Just before sacrifice, rats were anesthetized with intraperitoneal sodium pentobarbital (50 mg/kg). After adequate anesthesia was achieved, an incision was made in the midline of the upper abdomen. The cardiac apex was palpated through the diaphragm, and a 21-gauge needle attached to a short length of stiff, fluid-filled catheter was inserted into the LV cavity through the apex. Hemodynamics were allowed to stabilize for approximately 1 min, and pressure tracings were then recorded on a strip chart recorder at a paper speed of 100 mm/s. Representative pressure tracings are shown in Figure 1. Rats were allowed to breathe spontaneously during the pressure recordings.
Estimation of LV wall stress.
LV meridional wall stress was estimated using a modification of previously published methods (20,23). Briefly, LV pressure was recorded within 48 h of the final echocardiogram (as described in the previous section). LV internal dimensions and LV posterior wall thickness were measured from the M-mode echocardiogram. LV meridional wall stress (kdyn/cm2) was estimated as: wall stress = 0.334 x LV pressure x [LVD/(1 + PWT/LVD)], where LVD = LV internal dimension and PWT = posterior wall thickness measured in cm at end-systole. This formula assumes spherical LV geometry and uniform wall thickness.
Morphometric examination.
Perfusion-fixed tissues from eight rats (two rats in each group) were examined morphometrically. Methods were similar to those previously described (14). Briefly, the hearts were excised and retrogradely perfused through the ascending aorta at 80–100 mm Hg pressure with the use of gravity flow with saline, followed by modified Karnofsky fixative (2% glutaraldehyde and 2% paraformaldehyde in phosphate buffer) for 5 minutes. Horizontal short-axis sections through the mid-left and right ventricles were dehydrated through an ethanol series, embedded in paraffin sectioned at 5-µm thickness, and stained with hematoxylin-eosin, and picric acid sirius red F3BA. Quantitative analysis was accomplished by light microscopy with a video-based image-analyzer system. Collagen volume percent was quantitatively evaluated at high power (x10 objective, x300 video-screen magnification) for interstitial collagen. The endocardial half of the LV myocardium was examined by use of the picrosirius red–stained sections and a 540-nm (green) filter to provide contrast of the collagen with the background. Using digitized images collected by the video camera, the volume percent collagen was determined on 20–30 randomly selected fields at high power, and the mean value was calculated for each animal. Myocyte cross-sectional area was quantitated in the 1-µm methacrylate sections stained with silver by digitizing a minimum of 100 myocyte cross-sectional areas. All myocytes were measured in subepicardial regions judged to be cut normal to the long axis of the cells by the nearly round shape of perfused capillaries in the region. All morphometric measurements were performed in a blinded manner. Results are presented as the mean ± SEM values computed from the average of individual measurements obtained from each heart.
Statistical analysis.
All values are shown as mean ± SEM. Main effects (group, time, and interaction of group and time) were tested using a two-factor ANOVA for repeated measures followed by Fisher’s protected least significant difference test for between-group comparisons. Differences at specific time points (between groups and within groups) were assessed using one-factor ANOVA with post hoc comparisons by Fisher’s protected least significant difference test. Correlation coefficients were obtained using linear regression (the method of least squares). A p of <0.05 was considered significant.
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Results
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Early effects of pressure overload.
At 6 weeks after banding, increases in anterior and posterior LV wall thicknesses and LV mass were seen in both male and female banded rats (Table 1), compared with same-sex sham operated controls. However, wall thicknesses and diastolic LV diameter normalized to body weight were greater in female than in male banded rats, reflecting underlying sex differences. When these parameters are expressed as a percent of same-sex sham averages, the differences disappeared.
The extent of hypertrophy was similar when examined as LV mass normalized to body weight. LV mass normalized to body weight and expressed relative to that seen in same-sex shams also failed to demonstrate sex differences. Female banded rats tended to have a higher relative wall thickness, as evidence of concentric remodeling, than males, although this did not reach statistical significance (p = 0.06).
Examination of LV function shows that pressure overload, at least at this early stage, had little effect on ejection phase indexes of systolic function, as measured by either midwall or endocardial shortening, when compared with shams. Wall stress was not significantly elevated in male and female banded rats, consistent with the preserved ejection phase indices. Together, these provide evidence of adequate compensation at this early stage of hypertrophy. Elevation of diastolic LV pressure was evident only in male rats when compared with same-sex shams.
Late effects of pressure overload.
At 20 weeks after banding (23–24 weeks of age), hypertrophy continued to increase as measured by LV mass in both male and female rats (Table 2). While LV mass/BW alone or expressed as a multiple of sham values were not different between male and female banded rats, LV mass/BW tended to fall over time in male banded rats, while it continued to rise in female banded rats (Fig. 2A). Female rats continued to show concentric remodeling (high relative wall thickness) when expressed as a percentage of same-sex sham values, while male rats did not. This finding is likely due to the increasing LV diastolic diameter seen only in male rats, which provides evidence of dilation and is an early marker for the transition to failure in this model (13,20).
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Figure 2 A, Echocardiographic LV mass normalized to body weight at 6 and 20 weeks after aortic banding in male and female rats. While this ratio tended to decrease in male rats, it continued to increase in female rats. B, In vivo LV systolic pressure 6 and 20 weeks after aortic banding in male and female rats. While LV pressure increased in females, it tended to decrease in males. Open squares = female; solid squares = male.
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Although both endocardial and midwall fractional shortening were preserved, male LVH rats showed signs of early systolic dysfunction, with rising wall stress and a tendency towards falling (rather than rising) LV systolic pressure (Fig. 2B). Elevation of LV diastolic pressure was more pronounced in males and was not seen in females. The pattern of abnormal diastolic filling or restriction became more marked in both males and females; however, the deceleration of rapid filling was significantly different from same-sex controls only in male banded rats.
Morphometry performed at 20 weeks revealed increased myocyte cross-sectional area in banded rats, especially males (Table 3). Collagen content was also increased and tended to be higher in males. The small number of animals examined precludes statistical analysis.
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Discussion
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Using a model of gradually imposed pressure overload produced by ascending aortic banding of weanling rats, we found significant sex differences in the evolution of the response to pressure overload. Early on, male and female rats show similar increases in LV mass and similar concentric remodeling. However, 3 months later, male rats show LV cavity dilation, loss of concentric remodeling, and elevated wall stress, which is subtle, but clear evidence that pathologic remodeling and the process of transitioning to heart failure has begun (13,20). Contributing to this process was inadequate hypertrophy in male banded rats; from 6 to 20 weeks, LV mass/body weight fell from 3.9 to 3.7 mg/g, while it rose from 4.2 to 4.7 mg/g in female banded rats. The changes seen in the male rats are identical to those repeatedly observed with this model, which we have documented as representing a transition from compensated pressure overload to early heart failure (13,20,24,25). Thus, male, but not female, rats demonstrate evidence of decompensation in the adaptation to pressure-overload hypertrophy 20 weeks after ascending aortic banding.
Transition to heart failure.
Although pathologic remodeling has long been postulated to herald the transition from a compensated state to failure, proof of this process has been difficult (26,27). However, using the same model as the present study (aortic banding in weanling rats), we have recently demonstrated that cavity dilation and early diastolic abnormalities herald the development of failure (20), as does a falling LV mass/body weight ratio (24). Biochemical and genetic markers parallel these structural and functional changes in this model (13–19,25), and include, in the compensated phase, increased LV ACE mRNA levels and activity and reexpression of the fetal gene program, including beta-myosin heavy chain, alpha-skeletal actin, and ANF. With the transition to hypertrophy, a progressive reduction in message levels of SERCA-2 and calcium uptake are noted, along with cavity dilation, early systolic and diastolic abnormalities, and premature death. Thus, the value of this model in the study of pressure overload hypertrophy is well established.
Early in the hypertrophic process, sex-related differences are limited. Instead, these develop over time, suggesting that the process of hypertrophic remodeling, and perhaps even the transition to failure, is modified by sex. Evidence supporting this hypothesis is found in humans in both aortic stenosis and hypertension, and in animal models of pressure overload hypertrophy. Older women and those with hypertension show a greater increase in LV mass than men, for any given blood pressure (elevation in afterload) (28,29), but no differences in the pattern of remodeling (30). Women with aortic stenosis have greater hypertrophy, more concentric remodeling, and better preserved LV function than do men (1,2–6). In particular, Villari et al. (2) found men with aortic stenosis to have more abnormalities in collagen architecture (endocardial fibrosis, increased cross-hatching) and passive elastic properties. Female spontaneously hypertensive rats demonstrate greater concentric remodeling and better systolic function than do males (7,8), as do transgenic mice with cardiac-specific expression of an identical mutant myosin heavy chain (31). Our findings in aortic-banded animals are similar, and use of a mechanical pressure overload model eliminates most other influences, including genetic sex-related differences in the SHR phenotype, or variables limiting clinical studies such as the duration and severity of pressure overload, concomitant coronary artery disease or hypertension, or aging.
"Supranormal" shortening and inappropriate hypertrophy have been described in subsets of elderly women with aortic stenosis (1,3). Our data show trends towards both in the female LVH rats, who, at 6 weeks, had a fractional shortening 6 points higher than either sham females or LVH males (49% vs. 43% in the other two groups), and relative wall thickness of 54, compared with 42 in sham females and 46 in LVH males. While small numbers precluded these changes from reaching statistical significance, these parallels with human disease further support our findings. Interestingly, a recent study described a significant rate of myocyte death with aging in men, but not in women (12), suggesting a mechanism by which the observed gender differences might occur.
The possible cause of sex differences in response to pressure overload can only be speculated upon. To date, sex differences in myocardial composition, biochemistry, and energetics have not been extensively studied even in normal animals; our data suggest differences exist in disease states. One study, in Lyon hypertensive rats, matched control of hypertrophy but not hypertension to a locus in the X chromosome (32). Gonadal hormones are known to affect the maintenance of normal heart weight, but exogenous administration did not influence the development of either physiologic or pathologic hypertrophy (33). Perhaps the underlying gender differences in body and heart size influence adaptation to pressure overload. A more likely possibility is that estrogen may be a transcriptional regulator of genes implicated in hypertrophy, including myosin heavy chain isoforms and structural matrix proteins (34–38). Preliminary data from our laboratory using the ascending aortic band model (39,40) suggest gender differences in the upregulation of beta-myosin heavy chain, consistent with these previous reports. A final possibility may lie in relationships between gender, estrogen, and the renin-angiotensin system, just starting to be explored, which suggest that estrogen may regulate angiotensin mRNA levels and ACE activity (41–44). Again, our laboratory’s preliminary findings of a greater upregulation of ACE mRNA levels in females with aortic banding is also consistent with this hypothesis (39,40). Gonadal hormones’ influence on cardiac growth per se are incompletely studied, and results are conflicting in animal models (33,45).
Limitations.
The method used for estimating LV wall stress is limited by the fact that pressure and chamber geometry were not measured simultaneously, were obtained using different anesthetic agents, and that peak LV systolic pressure may not coincide temporally with peak posterior wall thickening measured by echocardiography. Despite these problems, the methodology was similar in all rats, so that comparisons between the groups are of interest. Using peak LV systolic pressure as an index of LV afterload is also problematic, since pressure alone does not take into account the pulsatile components of afterload.
Study of animals of different and changing body size is complex, as heart size can vary significantly. Accordingly, we normalized data in two ways: to body weight and as a percent of the average value in same-sex shams. We felt that using body weight alone failed to account for possible gender differences in control animals, a concern that is validated by the sex-specific cut-off values in LV mass known to be required for identification of hypertrophy in humans (46,47). Use of tibial length for normalization possesses the same limitations. Normalization to same-sex control values not only corrects for sex-related differences, but those that occur with normal growth and aging, a particularly important consideration when using young animals, and eliminates concerns regarding the influences of underlying gender differences contributing to our findings in pressure overload.
No formal sample size calculations were performed, as we did not know what magnitude of difference to expect between males and females. These data may therefore serve to guide future investigators in this area.
Clinical implications.
Our study demonstrates that the process of cardiac adaptation to pressure overload differs in male and female rats. These results amplify similar findings reported in humans, in whom other influences could not be excluded, confirming that sex does indeed play an important role in cardiac disease states.
Combined with prior studies in this well-characterized model, the present results suggest that the hormonal and biochemical milieu in males alters the adaptation to pressure overload in such a way as to predispose towards an earlier transition to heart failure. Clinically, differences in compensatory adaptation to pressure overload may impact the intensity of care and follow-up patients receive, as well as the need for and type of intervention. Our data suggest that a more aggressive approach to the treatment of pressure overload and early detection of the transition to failure may be warranted in men. The impact of such a strategy on ventricular function and hypertrophy, and ultimately on disease progression, remains to be proven.
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Acknowledgments
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We thank Mr. Souen Ngoy for his assistance in surgical preparation of the animals, and Deborah Dimond for her excellent secretarial assistance.
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Footnotes
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This study was supported in part by NHLBI Grant HL-52864 (Dr. Lorell, Dr. Weinberg, and Dr. Douglas).
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