Effects of dietary phytoestrogens on cardiac remodeling secondary to chronic volume overload in female rats

Previously, we demonstrated that intact female rats fed a standard rodent diet containing soybean products exhibit essentially no adverse left ventricular (LV) remodeling in response to aortocaval fistula-induced chronic volume overload. We hypothesized that phytoestrogenic compounds in the diet contributed to the female cardioprotection. To test this hypothesis, four groups of female rats were studied: sham-operated (Sham) and fistula (Fist) rats fed a diet with [P(+)] or without [P(−)] phytoestrogens. Eight weeks postfistula, systolic and diastolic cardiac function was assessed by using a blood-perfused, isolated heart preparation. High-phytoestrogen diet had no effect on body, heart, and lung weights, or cardiac function in Sham rats. Fistula groups developed LV hypertrophy, which was not reduced by dietary phytoestrogens [1,184 ± 229 mg Fist-P(−) and 1,079 ± 199 mg Fist-P(+) vs. 620 ± 47 mg for combined Sham groups, P < 0.05]. Unstressed LV volume increased in Fist-P(−) rats (428 ± 16 vs. 300 ± 14 μl Sham, P < 0.0001), but it was not different from Sham for Fist-P(+) animals (286 ± 17 μl). Fist-P(−) rats developed increased ventricular compliance (5.3 ± 0.8 vs. 2.3 ± 0.3 μl/mmHg Sham, P < 0.01), whereas Fist-P(+) rats had no change in compliance (2.8 ± 0.4 μl/mmHg). Intrinsic ventricular contractility was maintained in the Fist-P(+) rats, but it was reduced ( P < 0.001) in the Fist-P(−) rats [systolic pressure-volume slope: 1.04 ± 0.03, 0.60 ± 0.06, and 0.99 ± 0.08 mmHg/μl, for Fist-P(+), Fist-P(−), and Sham, respectively]. These data indicate that dietary phytoestrogens contribute significantly to female cardioprotection against volume overload-induced adverse ventricular remodeling and that studies evaluating gender differences in cardiovascular remodeling must consider the influence of dietary phytoestrogens.

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Cardioprotection in female rats subjected to chronic volume overload: synergistic interaction of estrogen and phytoestrogens

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00281.2007 ◽

2008 ◽

Vol 294 (1) ◽

pp. H198-H204 ◽

Cited By ~ 28

Author(s):

Jason D. Gardner ◽

Gregory L. Brower ◽

Tetyana G. Voloshenyuk ◽

Joseph S. Janicki

Keyword(s):

Ventricular Remodeling ◽

Isolated Heart ◽

Volume Overload ◽

Ovarian Hormones ◽

Left Ventricular ◽

Receptor Expression ◽

Female Rats ◽

Ovariectomized Rats ◽

Lv Remodeling ◽

Chronic Volume Overload

Intact female rats fed a high-phytoestrogen diet are protected against adverse left ventricular (LV) remodeling induced by chronic volume overload. We hypothesized that both phytoestrogens and ovarian hormones, particularly estrogen, are necessary for this dietary-induced cardioprotection. To test this hypothesis, eight groups of female rats were studied; rats were fed either a high-phytoestrogen (+phyto) or phytoestrogen-free diet. Groups included sham-operated rats, intact rats with fistula (Fist), ovariectomized rats with fistula (Fist-OX), and Fist-OX rats treated with estrogen (EST). Myocardial function and remodeling were assessed after 8 wk of volume overload using a blood-perfused isolated heart apparatus. Fist-OX rats developed significant ventricular dilatation and increased compliance vs. intact Fist rats, which were associated with a significant decrease in contractility. Estrogen treatment prevented pulmonary edema and attenuated LV hypertrophy and dilatation but did not maintain contractility. However, dietary phytoestrogens completely prevented LV dilatation in both the Fist+phyto and Fist-OX+EST+phyto groups but had no effect on LV remodeling in the Fist-OX+phyto group. Contractility was significantly greater in the estrogen-treated rats fed the phytoestrogen diet than in those treated with estrogen alone. Dietary phytoestrogens did not affect LV or uterine mass, serum estrogen, LV estrogen receptor expression, or cardiac function in sham animals. These data indicate that estrogen is not solely responsible for the cardioprotection exhibited by intact females and that phytoestrogens can work synergistically with ovarian hormones to attenuate ventricular remodeling induced by chronic volume overload in female rats.

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Estrogen receptor antagonism exacerbates cardiac structural and functional remodeling in female rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00348.2016 ◽

2017 ◽

Vol 312 (1) ◽

pp. H98-H105 ◽

Cited By ~ 3

Author(s):

M. C. El Hajj ◽

V. K. Ninh ◽

E. C. El Hajj ◽

J. M. Bradley ◽

J. D. Gardner

Keyword(s):

Estrogen Receptor ◽

Ventricular Remodeling ◽

Volume Overload ◽

Wall Stress ◽

Left Ventricular ◽

Female Rats ◽

Ovariectomized Rats ◽

Receptor Antagonism ◽

Functional Changes ◽

Chronic Volume Overload

We have previously demonstrated the cardioprotective effects of ovarian hormones against adverse ventricular remodeling imposed by chronic volume overload. Here, we assess the estrogen receptor dependence of this cardioprotection. Four groups of female rats were studied: sham-operated (Sham), volume overloaded [aortocaval fistula (ACF)], Sham treated with estrogen receptor antagonist ICI 182,780 (Sham + ICI), and ACF treated with ICI. Cardiac function was assessed temporally using echocardiogram, and tissue samples were collected at 5 days and 6 wk postsurgery. All rats with volume overload had significantly increased cardiac output (96 ± 32 ml/min for ACF and 108 ± 11 ml/min for ACF + ICI vs. 31 ± 2 for Sham, P < 0.05). At 6 wk, volume overload induced significant left ventricular (LV) hypertrophy in both untreated and treated ACF groups. Both ACF groups developed significantly increased LV end-diastolic diameter (LVEDD), indicating LV dilatation, with the ACF + ICI group having the greatest increase (340%, relative to Sham). Ejection fraction was significantly reduced in the ACF + ICI group (23% reduction) at 6 wk postsurgery compared with untreated ACF ( P < 0.05). Interstitial collagen staining was significantly reduced by volume overload, with estrogen receptor antagonism causing greater collagen loss at both 5 days and 6 wk postsurgery. Furthermore, volume overload induced a significant increase in LV wall stress only in rats treated with estrogen antagonist. These data indicate that estrogen receptor signaling is essential for sex hormone-dependent cardioprotection against adverse remodeling. The maintenance of myocardial extracellular matrix collagen appears to play a key role in this cardioprotection. NEW & NOTEWORTHY We assessed the estrogen receptor (ER) dependence of female-specific cardioprotection using a rat model of chronic volume-overload stress. ER antagonism worsened ventricular wall stress, ventricular dilation, and cardiac dysfunction induced by volume overload. Further, blocking ERs resulted in cardiac remodeling and functional changes similar to that previously found in ovariectomized rats.

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Temporal evaluation of left ventricular remodeling and function in rats with chronic volume overload

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1996.271.5.h2071 ◽

1996 ◽

Vol 271 (5) ◽

pp. H2071-H2078 ◽

Cited By ~ 43

Author(s):

G. L. Brower ◽

J. R. Henegar ◽

J. S. Janicki

Keyword(s):

Ventricular Remodeling ◽

Diastolic Pressure ◽

Systolic Function ◽

Left Ventricular Remodeling ◽

Isolated Heart ◽

Volume Overload ◽

Left Ventricular ◽

Control Value ◽

Chronic Volume Overload ◽

And Function

The left ventricle (LV) significantly dilates and hypertrophies in response to chronic volume overload. However, the temporal responses in LV mass, volume, and systolic/diastolic function secondary to chronic volume overload induced by an infrarenal arteriovenous (A-V) fistula in rats have not been well characterized. To this end, LV end-diastolic pressure, size, and function (i.e., isovolumetric pressure-volume relationships in the blood-perfused isolated heart) were assessed at 1, 2, 3, 5, and 8 wk post-A-V fistula and compared with age-matched control animals. Progressive hypertrophy (192% at 8 wk), ventricular dilatation (172% at 8 wk), and a decrease in ventricular stiffness (257% at 8 wk) occurred in the fistula groups. LV end-diastolic pressure increased from a control value of 4.2 +/- 3.1 mmHg to a peak value of 15.7 +/- 3.6 mmHg after 3 wk of volume overload. A subsequent decline in LVEDP to 11.0 +/- 6.0 mmHg together with further LV dilation (169%) corresponded to a significant decrease in LV stiffness (222%) at 5 wk post-A-V fistula. Myocardial contractility, as assessed by the isovolumetric pressure-volume relationship, was significantly reduced in all A-V fistula groups; however, the compensatory remodeling induced by 8 wk of chronic biventricular volume overload tended to preserve systolic function.

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Estrogen attenuates chronic volume overload induced structural and functional remodeling in male rat hearts

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00336.2009 ◽

2010 ◽

Vol 298 (2) ◽

pp. H497-H504 ◽

Cited By ~ 48

Author(s):

Jason D. Gardner ◽

David B. Murray ◽

Tetyana G. Voloshenyuk ◽

Gregory L. Brower ◽

Jessica M. Bradley ◽

...

Keyword(s):

Ventricular Remodeling ◽

Volume Overload ◽

Left Ventricular ◽

Estrogen Treatment ◽

Female Rats ◽

Male Rats ◽

Ventricular Dilatation ◽

Matrix Metalloproteinase 2 ◽

Male Rat ◽

Chronic Volume Overload

We have previously reported gender differences in ventricular remodeling and development of heart failure using the aortocaval fistula model of chronic volume overload in rats. In contrast to males, female rats exhibited no adverse ventricular remodeling and less mortality in response to volume overload. This gender-specific cardioprotection was lost following ovariectomy and was partially restored using estrogen replacement. However, it is not known if estrogen treatment would be as effective in males. The purpose of this study was to evaluate the structural and functional effects of estrogen in male rats subjected to chronic volume overload. Four groups of male rats were studied at 3 days and 8 wk postsurgery as follows: fistula and sham-operated controls, with and without estrogen treatment. Biochemical and histological studies were performed at 3 days postsurgery, with chronic structural and functional effects studied at 8 wk. Measurement of systolic and diastolic pressure-volume relationships was obtained using a blood-perfused isolated heart preparation. Both fistula groups developed significant ventricular hypertrophy after 8 wk of volume overload. Untreated rats with fistula exhibited extensive ventricular dilatation, which was coupled with a loss of systolic function. Estrogen attenuated left ventricular dilatation and maintained function in treated rats. Estrogen treatment was also associated with a reduction in oxidative stress and circulating endothelin-1 levels, as well as prevention of matrix metalloproteinase-2 and -9 activation and breakdown of ventricular collagen in the early stage of remodeling. These data demonstrate that estrogen attenuates ventricular remodeling and disease progression in male rats subjected to chronic volume overload.

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Permanent changes of ventricular contractility and compliance in chronic volume overload

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1979.237.5.h575 ◽

1979 ◽

Vol 237 (5) ◽

pp. H575-H583

Author(s):

W. W. Pinsky ◽

R. M. Lewis ◽

C. J. Hartley ◽

M. L. Entman

Keyword(s):

Diastolic Pressure ◽

Vena Cava ◽

Volume Overload ◽

Ventricular Volume ◽

Left Ventricular ◽

Segment Length ◽

Myocardial Segment ◽

Ventricular Contractility ◽

Beta Adrenergic ◽

Ventricular Compliance

Left ventricular volume overload (LVVO) has been created in 18 dogs by anastomosing a Dacron conduit between the infrarenal abdominal aorta and inferior vena cava. The dogs previously were instrumented so that in the awake state LV pressure, systemic arterial pressure, LV dP/dt, myocardial segment length and excursion, and coronary and renal artery velocities could be monitored. The animals were stressed with separate infusions of alpha-adrenergic and beta-adrenergic agonists. Both at rest and with stress, over a 12-wk period, preejection, ejection, and contractility indices decreased. Left ventricular compliance decreased as exemplified by the increased ratio of end-diastolic pressure to end-diastolic length. The shunt was ablated in 7 dogs, and monitoring in conjuction with alpha- and beta-adrenergic stress foan additional 12 wk demonstrated an initial improvement in the previous indices. However, the amelioration plateaued and values similar to the control state were not attained. This suggests that potentially permanent alterations in ventricular function and compliance have occurred.

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A Bioengineered Neuregulin-Hydrogel Therapy Reduces Scar Size and Enhances Post-Infarct Ventricular Contractility in an Ovine Large Animal Model

Journal of Cardiovascular Development and Disease ◽

10.3390/jcdd7040053 ◽

2020 ◽

Vol 7 (4) ◽

pp. 53

Author(s):

Jeffrey E. Cohen ◽

Andrew B. Goldstone ◽

Hanjay Wang ◽

Brendan P. Purcell ◽

Yasuhiro Shudo ◽

...

Keyword(s):

Cardiac Function ◽

Systolic Pressure ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Coronary Artery Ligation ◽

Large Animal ◽

Ventricular Contractility ◽

Intramyocardial Injection ◽

Ventricular Ejection Fraction ◽

Scar Size

The clinical efficacy of neuregulin (NRG) in the treatment of heart failure is hindered by off-target exposure due to systemic delivery. We previously encapsulated neuregulin in a hydrogel (HG) for targeted and sustained myocardial delivery, demonstrating significant induction of cardiomyocyte proliferation and preservation of post-infarct cardiac function in a murine myocardial infarction (MI) model. Here, we performed a focused evaluation of our hydrogel-encapsulated neuregulin (NRG-HG) therapy’s potential to enhance cardiac function in an ovine large animal MI model. Adult male Dorset sheep (n = 21) underwent surgical induction of MI by coronary artery ligation. The sheep were randomized to receive an intramyocardial injection of saline, HG only, NRG only, or NRG-HG circumferentially around the infarct borderzone. Eight weeks after MI, closed-chest intracardiac pressure–volume hemodynamics were assessed, followed by heart explant for infarct size analysis. Compared to each of the control groups, NRG-HG significantly augmented left ventricular ejection fraction (p = 0.006) and contractility based on the slope of the end-systolic pressure–volume relationship (p = 0.006). NRG-HG also significantly reduced infarct scar size (p = 0.002). Overall, using a bioengineered hydrogel delivery system, a one-time dose of NRG delivered intramyocardially to the infarct borderzone at the time of MI in adult sheep significantly reduces scar size and enhances ventricular contractility at 8 weeks after MI.

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Time-dependent remodeling of transmural architecture underlying abnormal ventricular geometry in chronic volume overload heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00326.2004 ◽

2004 ◽

Vol 287 (5) ◽

pp. H1994-H2002 ◽

Cited By ~ 10

Author(s):

Hiroshi Ashikaga ◽

Jeffrey H. Omens ◽

James W. Covell

Keyword(s):

Wall Thickness ◽

Ventricular Remodeling ◽

Volume Overload ◽

Wall Stress ◽

Anterior Wall ◽

Left Ventricular ◽

Ventricular Geometry ◽

Final Study ◽

Chronic Volume Overload ◽

Apical Site

To test the hypothesis that the abnormal ventricular geometry in failing hearts may be accounted for by regionally selective remodeling of myocardial laminae or sheets, we investigated remodeling of the transmural architecture in chronic volume overload induced by an aortocaval shunt. We determined three-dimensional finite deformation at apical and basal sites in left ventricular anterior wall of six dogs with the use of biplane cineradiography of implanted markers. Myocardial strains at end diastole were measured at a failing state referred to control to describe remodeling of myofibers and sheet structures over time. After 9 ± 2 wk (means ± SE) of volume overload, the myocardial volume within the marker sets increased by >20%. At 2 wk, the basal site had myofiber elongation (0.099 ± 0.030; P < 0.05), whereas the apical site did not [ P = not significant (NS)]. Sheet shear at the basal site increased progressively toward the final study (0.040 ± 0.003 at 2 wk and 0.054 ± 0.021 at final; both P < 0.05), which contributed to a significant increase in wall thickness at the final study (0.181 ± 0.047; P < 0.05), whereas the apical site did not ( P = NS). We conclude that the remodeling of the transmural architecture is regionally heterogeneous in chronic volume overload. The early differences in fiber elongation seem most likely due to a regional gradient in diastolic wall stress, whereas the late differences in wall thickness are most likely related to regional differences in the laminar architecture of the wall. These results suggest that the temporal progression of ventricular remodeling may be anatomically designed at the level of regional laminar architecture.

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