Association of Female Menopause With Atrioventricular Mechanics and Outcomes

Abstract

Background: Despite known sex differences in cardiac structure and function, little is known about how menopause and estrogen associate with atrioventricular mechanics and outcomes.

Objective: To study how, sex differences, loss of estrogen in menopause and duration of menopause, relate to atrioventricular mechanics and outcomes.

Methods: Among 4051 asymptomatic adults (49.8 ± 10.8 years, 35%women), left ventricular (LV) and left atrial (LA) mechanics were assessed using speckle-tracking.

Results: Post-menopausal (vs. pre-menopausal) women had similar LV ejection fraction but reduced GLS, reduced PALS, increased LA stiffness, higher LV sphericity and LV torsion (all p < 0.001). Multivariable analysis showed menopause to be associated with greater LV sphericity (0.02, 95%CI 0.01, 0.03), higher indexed LV mass (LVMi), lower mitral e', lower LV GLS (0.37, 95%CI 0.04-0.70), higher LV torsion, larger LA volume, worse PALS (∼2.4-fold) and greater LA stiffness (0.028, 95%CI 0.01-0.05). Increasing years of menopause was associated with further reduction in GLS, markedly worse LA mechanics despite greater LV sphericity and higher torsion. Lower estradiol levels correlated with more impaired LV diastolic function, impaired LV GLS, greater LA stiffness, and increased LV sphericity and LV torsion (all p < 0.05). Approximately 5.5% (37/669) of post-menopausal women incident HF over 2.9 years of follow-up. Greater LV sphericity [adjusted hazard ratio (aHR) 1.04, 95%CI 1.00-1.07], impaired GLS (aHR 0.87, 95%CI 0.78-0.97), reduced peak left atrial longitudinal strain (PALS, aHR 0.94, 95%CI 0.90-0.99) and higher LA stiffness (aHR 10.5, 95%CI 1.69-64.6) were independently associated with the primary outcome of HF hospitalizations in post-menopause. Both PALS < 23% (aHR:1.32, 95%CI 1.01-3.49) and GLS < 16% (aHR:5.80, 95%CI 1.79-18.8) remained prognostic for the incidence of HF in post-menopausal women in dichotomous analyses, even after adjusting for confounders. Results were consistent with composite outcomes of HF hospitalizations and 1-year all-cause mortality as well.

Conclusion: Menopause was associated with greater LV/LA remodeling and reduced LV longitudinal and LA function in women. The cardiac functional deficit with menopause and lower estradiol levels, along with their independent prognostic value post-menopause, may elucidate sex differences in heart failure further.

Keywords: echocardiography; estrogen; heart failure; left atrial strain; menopause; remodeling; women.

FIGURE 1

Schematic flow diagram after exclusion and final selection of study population.

FIGURE 2

Definition of sphericity, strain, torsion and cardiac mechanics. Definition of LV sphericity (A) and the fraction of longitudinal systolic shortening [expressed as percentage (%)] in terms of longitudinal strain (B). When the heart contracts, the apex rotates in counterclockwise direction and the base rotates in clockwise direction. Cardiac torsion as defined by the net twist angle (from opposite rotational differences between base and apex) divided by LV length (L) (C). Curves from tracing of ventricular (D)/atrial longitudinal strain (E) from any single plane and calculation of twist from automatic quantification algorithm in current study were displayed (F).

FIGURE 3

Duration of menopause-associated changes in (A) increased LV mass-to-volume ratio (MV) and worsened global longitudinal strain (GLS) with relatively unchanged LV ejection fraction (LVEF), (B) sphericity at end-diastole accompanied by greater torsion despite worsened GLS and relatively unchanged global circumferential strain (GCS), (C) worsened myocardial relaxation e’, greater indexed LA volume and relatively unchanged LA emptying fraction (LAEF), (D) worsened global peak LA strain (PALS) and greater LA stiffness in post-menopause women with time to onset of menopause available.

FIGURE 4

Illustrative summary of hypothetical mechanisms of LV geometric and mechanical alterations in post-menopausal women in contrast to men and pre-menopausal women. cGMP, cyclic GMP; eNOS, endothelial nitric oxide synthase; GLS, global longitudinal strain; IL-6, cytokine interleukin-6; PALS, peak atrial longitudinal strain; TGF-β, transforming growth factor; TNF, tumor necrosis factor.