Changes in hemodynamics and left ventricular structure after menopause

doi:10.1016/S0002-9149(02)02193-8

The American Journal of Cardiology

Volume 89, Issue 7, 1 April 2002, Pages 830-833

https://doi.org/10.1016/S0002-9149(02)02193-8 Get rights and content

Abstract

To evaluate the cardiovascular changes associated with menopause, we studied hemodynamics at rest, ambulatory blood pressure, and left ventricular structure in a biracial cohort of pre- and postmenopausal women of similar age, race, weight, and blood pressure. Despite similar levels of blood pressure, postmenopausal women had a higher indexed peripheral resistance (2,722 ± 757 vs 2,262 ± 661 dynes·s·m²/cm⁵, p <0.01) and a lower cardiac index (2.64 ± 0.73 vs 3.10 ± 0.71 L/min·m², p <0.01) than premenopausal women. Postmenopausal women also had less nocturnal decreases in both systolic (15 ± 8 vs 19 ± 8 mm Hg, p <0.01) and diastolic (12 ± 6 vs 15 ± 6 mm Hg, p = 0.05) pressures during ambulatory monitoring and higher levels of hematocrit (40 ± 2% vs 38 ± 3%, p <0.01). In association with this greater hemodynamic load, postmenopausal women had evidence of early concentric left ventricular remodeling, manifested by a greater relative wall thickness (0.38 ± 0.06 vs 0.35 ± 0.06, p <0.01) than that observed in premenopausal women. Differences between pre- and postmenopausal women in hemodynamics, diurnal blood pressure variation, and left ventricular structure were observed in white and African-American subjects. These results suggest that menopause is associated with hemodynamic changes and left ventricular remodeling, which may contribute to the enhanced cardiovascular risk observed in postmenopausal women.

Section snippets

Methods

The protocol was approved by the Committee on the Protection of Rights of Human Subjects and written informed consent was obtained from all subjects before participation. The study population consisted of 118 employed volunteers between 47 and 55 years of age, recruited by advertisements in local newspapers. All had casual blood pressure on screening examination of <180/90 mm Hg. None were taking exogenous estrogen. Other exclusions included history of surgical menopause, diabetes mellitus,

Demographic characteristics:

The demographics of the pre- and postmenopausal women in the study cohort are listed in Table 1. Postmenopausal women were slightly older than premenopausal women, but otherwise the 2 groups were similar. The 91 subjects with interpretable echocardiograms did not differ from the cohort as a whole in any of these characteristics.

Hemodynamic profile, ambulatory blood pressure, and laboratory parameters:

Table 2 lists hemodynamic parameters, ambulatory blood pressures, and biochemical and hematologic data for both the pre- and postmenopausal women.

Blood pressures and

Discussion

Our study suggests that menopause is associated with concentric remodeling of the left ventricle (i.e., an increase in the ratio of left ventricular wall thickness to chamber size). In our analysis of pre- and postmenopausal women of similar ages who were matched for body size and blood pressure at rest, echocardiographic measurements of left ventricular mass were similar in the 2 groups. Postmenopausal women, however, had a significantly greater relative wall thickness. This pattern of left

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Significant role of estrogen in maintaining cardiac mitochondrial functions
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The roles of female sex hormones in the regulation of cardiovascular function have been recently re-evaluated due to disputation in the benefits of hormone replacement therapy in postmenopausal women. [1]. Increased ventricular wall thickness but decreased fractional shortening in the hearts of postmenopausal females compared to age-matched premenopausal controls independent of hypertension suggested potential direct actions of female sex hormones on cardiac muscle [2,3]. Many clinical trials have previously demonstrated an improvement in cardiac performance in postmenopausal females who received hormone replacement therapy [4–6].
Increased susceptibility to stress-induced myocardial damage is a significant concern in addition to decreased cardiac performance in postmenopausal females. To determine the potential mechanisms underlying myocardial vulnerability after deprivation of female sex hormones, cardiac mitochondrial function is determined in 10-week ovariectomized rats (OVX). Significant mitochondrial swelling in the heart of OVX rats is observed. This structural alteration can be prevented with either estrogen or progesterone supplementation. Using an isolated mitochondrial preparation, a decrease in ATP synthesis by complex I activation in an OVX rat is completely restored by estrogen, but not progesterone. At basal activation, reactive oxygen species (ROS) production from the mitochondria is not affected by the ovariectomy. However, after incubated in the presence of either high Ca²⁺ or antimycin-A, there is a significantly higher mitochondrial ROS production in the OVX sample compared to the control. This increased stress-induced ROS production is not observed in the preparation isolated from the hearts of OVX rats with estrogen or progesterone supplementation. However, deprivation of female sex hormones has no effect on the protein expression of electron transport chain complexes, mitofusin 2, or superoxide dismutase 2. Taken together, these findings suggest that female sex hormones, estrogen and progesterone, play significant regulatory roles in maintaining normal mitochondrial properties by stabilizing the structural assembly of mitochondria as well as attenuating mitochondrial ROS production. Estrogen, but not progesterone, also plays an important role in modulating mitochondrial ATP synthesis.
MicroRNA-23a mediates mitochondrial compromise in estrogen deficiency-induced concentric remodeling via targeting PGC-1α
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Concentric remodeling is induced most commonly by increasing afterload [7]. Whereas, the concentric remodeling of myocardium occurred in postmenopausal women is independent of hypertension or diabetes [6,8]. Therefore, here we hypothesize that E2 deficiency may induce a number of intrinsic cellular damages, such as mitochondrial dysfunction, in cardiomyocytes and subsequently promote cardiac remodeling.
It is well known that menopause could worsen age-related ventricular concentric remodeling following estrogen (E2) deficiency. However the underlying mechanisms of such phenomena are not fully understood. Mitochondria, as the ‘cellular power station’ of hearts, play an important role in maintaining normal cardiac function and structure. Therefore, the present study aims to investigate whether mitochondrial compromise is responsible for E2 deficiency associated concentric remodeling and, if so, what is its underlying molecular mechanism. We found evident concentric remodeling pattern in both postmenopausal and ovariectomized (OVX) mice, which could be attenuated by E2 replacement. Further study showed mitochondrial structural damages and respiratory function impairment in myocardium of both postmenopausal and OVX mice and E2 supplement reversed mitochondrial dysfunction in OVX mice, suggesting that E2 deficiency could induce mitochondrial compromise in the heart. Then, peroxisome proliferator-activated receptor-γ co-activator 1-α (PGC-1α), a key mitochondrial function and biology regulator, was found significantly reduced in both postmenopausal and OVX mice. The reduction of PGC-1α protein level in OVX mice could be rescued by E2 delivery, indicating that E2 could positively regulate PGC-1α expression. Next, we found that microRNA-23a (miR-23a) could be negatively regulated by E2 in both myocardium and cultured cardiomyocytes. Moreover, miR-23a could directly downregulate PGC-1α expression in cardiomyocytes via binding to its 3′UTR which implied that miR-23a could be critical for the downregulation of PGC-1α under E2 deficiency. Overexpression of miR-23a was also found to damage mitochondria in cultured cardiomyocytes, ascribed to PGC-1α downregulation. Taken together, E2 deficiency may cause mitochondrial compromise through miR-23a-mediated PGC-1α downregulation, which may subsequently lead to the menopause-associated concentric remodeling.
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^☆: This study was supported by grants HL-49427 and HL-53724 from the National Institutes of Health (NIH) and M01-RR-30 General Clinical Research Centers Program, National Center for Research Resources, NIH, Bethesda, Maryland.

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Changes in hemodynamics and left ventricular structure after menopause☆

Abstract

Section snippets

Methods

Demographic characteristics:

Hemodynamic profile, ambulatory blood pressure, and laboratory parameters:

Discussion

Am J Hypertens

Am J Cardiol

J Am Coll Cardiol

Lancet

Lancet

Am J Cardiol

Am J Cardiol

Am J Hypertens

Am J Cardiol

Am J Cardiol

Menopause and the risk of coronary heart disease in women

N Engl J Med

Menopause and coronary heart diseasethe Framingham study

Ann Intern Med

Early cardiac changes after menopause

Hypertension