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Impact of estradiol, testosterone and their ratio on left and right auricular myofilament function in male and female patients undergoing coronary artery bypass grafting

BMC Cardiovascular Disorders volume 23, Article number: 538 (2023) Cite this article

Abstract

Background

The impact of sex hormones on right and left auricular contractile apparatus function is largely unknown. We evaluated the impact of sex hormones on left and right heart contractility at the level of myocardial filaments harvested from left and right auricles during elective coronary artery bypass surgery.

Methods

150 patients (132 male; 18 female) were enrolled. Preoperative testosterone and estradiol levels were measured with Immunoassay. Calcium induced force measurements were performed with left- and right auricular myofilaments in a skinned fiber model. Correlation analysis was used for comparison of force values and levels of sex hormones and their ratio.

Results

Low testosterone was associated with higher top force values in right-sided myofilaments but not in left-sided myofilaments for both sexes (p = 0.000 in males, p = 0.001 in females). Low estradiol levels were associated with higher top force values in right-sided myofilaments (p 0.000) in females and only borderline significantly associated with higher top force values in males (p 0.056). In females, low estradiol levels correlated with higher top force values in left sided myofilaments (p 0.000). In males, higher Estradiol/Testosterone ratio (E/T ratio) was only associated with higher top force values from right auricular myofilaments (p 0.04) In contrast, in females higher E/T ratio was associated with lower right auricular myofilament top force values (p 0.03) and higher top force values in left-sided myofilaments (p 0.000).

Conclusions

This study shows that patients’ comorbidities influence left and right sided contractility and may blur results concerning influence of sex hormones if not eliminated. A sex hormone dependent influence is obvious with different effects on the left and right ventricle. The E/T ratio and its impact on myofilament top force showed divergent results between genders, and may partially explain gender differences in patients with cardiovascular disease.

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Introduction

Clinical and basic science studies have shown important sex differences in cardiac structure and function [1,2,3,4,5]. Although an impact of sex hormones is frequently discussed, data from basic science studies show conflicting results and cannot simply be extrapolated to clinical settings. Clinical studies mainly focus on functional and morphological differences between genders. Studies on humans evaluating the impact of sex hormones on contractility at the level of myocardial filaments are sparse and limited by small study populations [6,7,8]. The ambiguity of knowledge in this topic is described by Ventetuolo and Subramanya et al., who stated that estradiol and testosterone have important but controversial and in part unknown roles for left and right auricular function [9,10,11].

According to the available literature, it seems obvious that sex hormones may have a different impact on right and left auricular function. The MESA study (Multi-Ethnic Study of Atherosclerosis), which evaluated the correlation between serum level of sex hormones and RV and LV function and structure with cardiac MRI [9, 11] showed that women tended to have higher RVEF and lower RVSV, RV mass, RVEDV and RVESV than men [9]. However, concerning higher RV-EF, these data were derived from women with exogenous estradiol intake. Furthermore, higher testosterone levels were associated with greater RV mass and larger RV volumes in men but not in women [9]. The same group demonstrated that higher testosterone levels were associated with a modest increase in left auricular mass and possibly better LV function in both genders [11]. In contrast, high estradiol levels were only associated with increased LV mass in men.

Dai et al. recommended investigating the combination of estrogens and androgens together as a ratio taking into account that the imbalance of hormones might be an important factor for sex specific cardiac function [6]. The importance of the interaction between these sex hormones were underlined by data from the MESA study. This study proved that a high estradiol/testosterone ratio (/E/T ratio) was associated with lower RV volumes and presumably better RV function in men, which was not identified by single sex hormone analysis [9]. However, the impact of sex hormones, their ratio on the level of the contractile apparatus of the left and right ventricle was not evaluated.

To elucidate whether sex hormones and their ratio may influence the contractile apparatus we analyzed the impact of sex hormones and their ratio on the intrinsic functional state of human right and left auricular function by using calcium induced force measurements of skinned human fibers from the right and left auricle from patients with coronary heart disease undergoing elective coronary artery bypass grafting (CABG).

Methods

Study sample

The study included one hundred fifty patients undergoing elective on-pump CABG between January 2019 and September 2019. We excluded patients with valve pathologies, reoperations and emergency indications. Since the first regression analysis revealed, that patients with diabetes mellitus, atrial fibrillation and peripheral arterial disease develop significant lower top force values, we also excluded patients presenting these diagnoses and performed a second regression analysis. Metabolic syndrome included arterial hypertension, diabetes mellitus II, dyslipidemia and obesity (BMI > 30 kg/m2). Seventy-one patients remained for the second regression analysis (63 males and 8 females). All patients were informed about the aim of the study and gave their written consent to participate. The University Hospital ethics committee approved the study (IRB approval: 143/17-sc 6.10.2017).We collected clinical findings and preoperative blood samples, taken prior to induction of anesthesia. Blood samples were immediately sent to the laboratory and stored at -80 °C. All data were recorded pseudonymously in a departmental database.

Preoperative clinical chemistry included HbA1C, creatinine, glomerular filtration rate (GFR) and N-terminal pro brain natriuretric peptid (NT-proBNP). The blood samples for the measurement of Estradiol and Testosterone were routinely taken in the morning and at the same time for all patients. Estradiol and testosterone were measured with automated Immunoassay system (Cobas e601).

Tissue harvest

All patients underwent on pump aortocoronary bypass grafting (CABG). Right auricular tissue was resected for venous cannulation for institution of cardiopulmonary bypass. The left auricle was removed after aortic cross clamping and antegrade infusion of Buckberg blood cardioplegia for the purpose of stroke prevention (4 min).

Myofilament preparation

Our experimental setup has been described in full detail before [3, 4]. Briefly, the intraoperatively resected tissue was transported in ice-cold oxygenated cardioplegic solution, containing BDM (Sigma Aldrich Chemie GmbH, Steinheim, Germany). For the skinning procedure, the trabeculae were excised and permeabilized with Triton-X solution (Sigma Aldrich Chemie GmbH, Steinheim, Germany). The skinned myofilaments were then attached to a force transducer and a forceps and the experiments were conducted by immersing the myofilaments in twelve bowls with increasing calcium concentrations. The calcium concentration is displayed as logarithmic calcium concentration (pCa), which is a negative decadic logarithm. We started with the lowest calcium concentration at pCa 7.0 and increasing at 6.5, 6.0, 5.75, 5.5, 5.4, 5.3, 5.2, 5.1, 5.0, 4.75, 4.52. Length changes, recorded by the force transducer, were recorded and stored in a database.

Statistical methods

Exploratory data analysis included descriptive statistics as well as boxplots, histograms and kernel density estimates to visualize the distribution of force values and study variables. The five replicates of force measurements for each patient at a specific calcium concentration tissue sample were aggregated to means for all further statistical analyses. We used three parameters for the assessment of cardiac contractility: top force value, calcium sensitivity (calcium concentration of half maximal activation) and steepness of the curves defined as Hill slope. Data are presented as mean ± standard deviation. Sex hormones were analyzed as high and low sex hormone concentrations according to the mean value. Treshold was 22.8 pg/ml for 17ß-Estradiol and 3.7 ng/ml for testosterone. E/T ratio was grouped in center (Q2, Q3) and tails (Q1, Q4).

We used spline regression models to visualize the functional relationship between force values and the -log10 of the calcium concentrations series (7.0, 6.5, 6.0, 5.75, 5.5, 5.4, 5.3, 5.2, 5.1, 5.0, 4.75, 4.52). Calcium concentrations were transformed by a restricted cubic spline function with 6 knots placed based on Harrell’s recommended percentiles. All force pCa curves were fitted for measurements obtained from the left and right heart muscle separately. In addition to curves for the total population we fitted curves for subgroups to explore the impact of study variables (age, gender, BMI, Estradiol, testosterone, HbA1c, lung function (FEV), renal function (GFR), PAD, atrial fibrillation, diabetes, metabolic syndrome, EuroScore). Atrial fibrillation, diabetes mellitus and PAD significantly decreased force development of right- and left sided myofilaments and were subsequently excluded in a second regression analysis. The second parametric regression analysis excluding patients with atrial fibrillation, diabetes mellitus and PAD included 63 male and 8 female patients.

Curves for Estradiol and Testosterone were additionally fitted stratified by sex to explore whether hormones act differently on force in males and females. Continuous variables were categorized in 4 groups defined by quartiles of the observed distribution. Finally, we used non-linear regression to model the force values as a function of the -log10 of the calcium concentrations. As functional relationship we assumed a sigmoid form reflecting the Hill equation with four parameters [12]. One parameter (bottom force, i.e. the force at pCa = 7.0) was fixed to zero, the other three parameters (top force, pCa50 and Hill slope) were estimated from the data using nonlinear least-squares estimation. Top force quantifies the maximum force reached by the muscle sample stimulated at pCa = 4.52; pCa50 quantifies the calcium sensitivity of the muscle tissue sample as the concentration required for 50% of maximum force, whereas the Hill slope describes the slope of the curve at the midpoint pCa50. In addition, we calculated t-tests to compare the parameter estimates obtained from the different subgroups.

All statistical analyses were conducted using the software STATA (StataCorp. 2017. Stata Statistical Software: Release 15. College Station, TX: StataCorp LLC).

Results

The study cohort consisted of 150 patients (132 men (88%) and 18 women (12%). Demographic data are depicted in Table 1.

Table 1 Patient’s characteristics
Full size table

Both groups were comparable except for lower height (159.7 ± 5.4 cm versus 173.4 ± 6.5 cm, p < 0.00), and body surface area (1.8 ± 0.1 m2 versus 2.0 ± 0.2 m2, p < 0.00), better FEV1 (106.4 ± 20.4% versus 88.7 ± 18.4%, p = 0.003) and lower serum creatinine in women. Serum concentrations of estradiol and testosterone were significantly lower in women.

We observed higher top force values for left-sided myofilaments (p = 0.000) and decreased calcium sensitivity (pCa50, p = 0.044) in all patients compared to right –sided myofilaments (Fig. 1).

Fig. 1
figure 1

Force values of right heart myofilaments were lower than left side for all patients

Full size image

Calcium concentrations (negative decadic logarithm) dependent force development (mN).

However, steepness of the curve (Hill slope) did not differ between left- and right-sided myofilaments (p = 0.05).

We could not identify a significant impact of gender or age on right- or left myofilament contractility (Tables 2 and 3).

Table 2 Impact of gender on left and right heart contractility
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Table 3 Impact of low versus high age on left and right heart contractility
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Based on mean values we analyzed high and low sex hormone concentrations. Threshold was 22.8 pg/ml for 17ß-Estradiol and 3.7 ng/ml for testosterone (Tables 4 and 5).

Table 4 Impact of low and high (median as cut off) estradiol hormone levels on left and right heart contractility
Full size table
Table 5 Impact of low and high (median as cut off) Testosterone hormone levels on left and right heart contractility
Full size table

Low 17ß-estradiol levels were associated with higher top force in males’ right-sided myofilaments (p = 0.004). In women, a trend towards low 17ß-estradiol concentrations and higher top force values in right-sided myofilaments was observed (p = 0.052). 17ß-estradiol had no impact on left auricular myofilament top force values in both sexes.

There was a significant correlation of low testosterone serum concentration and higher top force values in right-sided myofilaments in males (p = 0.000) and females (p = 0.000). In contrast, there was no impact of testosterone on left-sided myofilament contractility.

E/T ratio analysis demonstrated (Table 6) that high E/T ratio was associated with higher top force in right-sided myofilaments in men (p = 0.023) but no effect on left-sided myofilaments. The E/T ratio had no effect on women’s right- or left-sided myofilament contractility.

Table 6 Sex hormone, E/T ratio and correlation to Top Force values
Full size table

Analysis of comorbidities (Table 7, at the end of document) showed a negative impact of atrial fibrillation on both left- and right-sided myofilaments, of peripheral arterial disease (PAD) on left-sided myofilaments and of diabetes mellitus on right-sided myofilaments.

Table 7 Influence of comorbidities on left and right heart contractility
Full size table

After exclusion of these confounders a second parametric regression analysis was performed and 71 patients remained (63 males and 8 females). Results are depicted in Table 8 (at the end of document).

Table 8 Regression analysis after exclusion of patients with atrial fibrillation, peripheral arterial disease and diabetes mellitus II
Full size table

Low estradiol values were associated with borderline higher force values in right-sided myofilaments of men (p = 0.056) but not in left-sided myofilaments (p = 0.1). In women low estradiol was associated with higher top force values in both right- and left-sided myofilaments.

Low testosterone levels correlated with higher top force values in both men’s and women’s right-sided myofilaments only.

Higher top force values were noted in right-sided myofilaments of male patients with higher E/T ratios (p 0.04). In women, higher E/T ratio was associated with higher top force values in left-sided myofilaments (p 0.000) but lower top force values in right-sided myofilaments.

Discussion

To the best of our knowledge, this is the first study to describe the impact of 17ß-estradiol, testosterone serum concentration and their ratio on the contractile function of left and right auricular myofilaments in patients scheduled for aortocoronary bypass grafting.

We found that low estradiol serum levels were associated with higher force values in right-sided myofilaments in men and women. Since diabetes mellitus, AF and POD had a negative effect on force development of both right and left auricular myofilaments these patients’ samples were excluded from further testing. The negative inotropic effect of these comorbid factors has been described before [13,14,15,16].

After exclusion of samples from such patients low 17ß-estradiol was associated with higher left auricular top force values in women, but not in men. In contrast, right auricular top force values revealed higher values with low 17ß-estradiol in both genders. Low testosterone was associated with higher right auricular myofilament top force values in both men and women. There was no effect of testosterone on left-sided myofilament force values. In men higher E/T ratio was associated with higher top forces in right auricular myofilaments only. For women higher E/T ratio was associated with higher top force values in left-sided but lower top force values in right-sided myofilaments.

Our results correspond with previous studies. Sitzler et al. observed a negative inotropic effect on force development after exposure to 17ß Estradiol in human right atrial tissue samples [8]. In his study, addition of testosterone on the specimen had no effect on contractility leading to the assumption of a calcium antagonistic effect, possibly due to interaction with 1,4 dihydropyridine binding site of L-type calcium channels, of 17ß estradiol on right atrial myofilaments [8, 17, 18]. Jiang et al. showed an inhibition of the slow calcium inward current induced by 17ß-estradiol in isolated guinea-pig ventricular myocytes [19], This inhibition was not present after exposure to testosterone, supporting a negative inotropic effect of 17ß-estradiol [8, 17,18,19]. This effect might contribute to the reduced force values associated with higher estradiol concentrations in our study group. But furthermore estradiol also seems to have a direct effect on the contractile proteins, since estradiol seems to attenuate atrial essential myosin light chain expression in cardiomyocytes exerting a negative inotropic effect [20].

Ventetuolo et al. observed genetic variations in estradiol metabolism associated with right auricular morphology. This supports our results that an effect of 17ß estradiol was present on right atrial myofilaments only. The observed effect of higher testosterone concentrations leading to low top force values in right atrial myofilaments from both sexes can be due to an inflammatory effect of testosterone with subsequent cardiac remodeling and reduced RV function [3, 21, 22]. Furthermore, the presence of different modifications of androgen receptor genotypes in men associated with reduced RVEF may support our results [10]. We did not find any association of lower testosterone and force values in left auricular myofilaments in either gender. Testosterone may influence L-type calcium channels [23, 24]. However contradictory observation s about the effect of testosterone on L-type calcium channels have been published [23, 24]. Golden et al. reported an increase of mRNA levels of L-type calcium channels after testosterone application, which might indicate increased contractility [23]. In contrast Gupte et al. showed that testosterone metabolites blocks L-type calcium channels in isolated rat hearts with Langendorff perfusion and inhibits cardiac contractility [25]. Moreover, testosterone acts not only via androgen receptors but also via genomic pathways [26].

Thus conflicting results clearly demonstrate that the influence of testosterone on cardiac contractility is not fully understood and that further research is mandatory.

Since sex hormones interact, their balance could be more relevant than single hormone serum concentration and assessment of E/T ratio on myocardial performance a valuable process [6]. In our study population higher E/T ratio was associated with higher right auricular top force values in men but had no effect on left auricular myofilaments. In contrast, a higher E/T ratio in women correlated with reduced right auricular top force values and higher left auricular top force values indicating a gender and side (right atrial or left atrial) specific effect. The effect of E/T ratio in men is supported by Ventetuolo et al. They showed that higher E/T ratio was associated with lower RV volume in men, implicating better RV function [9]. Since human studies concerning sex hormones and their impact on myocardial contractility in women are lacking, one has to rely on animal studies up to now.

However, these results are even more conflicting. A positive effect of 17ß estradiol on cardiac contractility was reported with different animal models [27,28,29,30,31]. In all models ovariectomy had no effect on cardiac function. Subsequent estrogen replacement had either no effect or resulted in reduced cardiac function [27,28,29,30,31]. One has to consider if results from animal models might be species specific, since myosin isoenzymes and contractility are species-specific. Therefore, these results may only be partially applicable to humans [32].

Limitations

Several limitations must be noted. First, despite being one of the largest studies with human tissue, the sample size is still too small to draw firm conclusions concerning the influence of sex hormones on left and right auricular myofilaments. This limits the statistical power of the results concerning E/T ratio in the female group. Furthermore the female sample size is very small and the advanced age combined with the postmenopausal hormone status is not representative for all females, which might have influenced the results. Second, a possible impact of hormone replacement therapy or hysterectomy/ ovariectomy on cardiac function and hormone status could be of high interest, however none of our patients received hormone replacement therapy or underwent hysterectomy or ovariectomy. We cannot exclude that medication like ACE inhibitors, which decrease pre- and afterload, might have influenced the contractile behavior of the skinned fibers through decreased wall stress. Third, we used human atrial tissue from left and right auricle. If these results can be extrapolated to ventricular tissue still is a matter of discussion although Vannier et al. observed similar contractile properties of human atrial and ventricular tissue thereby concluding a transferability of these results to ventricular tissue [33]. Fourth, all female patients in our study were postmenopausal, so 17ß-estradiol serum values were decreased and analyzed with a mean cut off. A control group of premenopausal women would be desirable to assess differences of 17ß-estradiol on contractility. Furthermore, the total number of women was low in our study, reflecting a well-known great dilemma of studies. Fifth, previous myocardial infarction as well as reduced left ventricular function in fermales might have also influenced the contractile properties of the myofilaments. Sixth, operator-specific treatment of the tissue samples with possible damage to the trabeculae cannot be excluded, although harvesting protocols were designed with a high degree of standardization. Seventh, we cannot estimate the influence of pathologic conditions like coronary heart disease, a chronic disease associated with inflammation, as an impact factor on cardiac properties of the myofilaments in opposite to normal physiological conditions. We have to admit restrictively that the observed correlations of sex hormones and cardiac function on level of the myofilaments might differ in healthy persons without cardiac disease.

Despite these limitations our study may serve as catalyst for future mechanistic and observational studies to define the influence of sex hormones on right and left heart contractility.

Conclusions

In summary, patients’ comorbidities influence left and right sided contractility and may disguise or eliminate the effect of sex hormones on cardiac contractility. A sex hormone dependent influence is evident with different effects on the left and right ventricle. The E/T ratio and its impact on myofilament top force values showed divergent results for men and women and may partially explain gender differences in patients with cardiovascular disease.

Our preliminary results should trigger further studies on the impact of sex hormones on cardiac contractility in a gender-dependent manner.

Data Availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

ADMA:

Asymmetric Dimethylarginine

AF:

Atrial fibrillation

BMI:

Body mass index

CABG:

Coronary artery bypass grafting

CAD:

Coronary Artery Disease

CRP:

C-reactive protein

DM:

Diabetes mellitus

E/T ratio:

17ßEstradiol/Testosterone ratio

GFR:

Glomerular filtration rate

HbA1C:

Glycated haemoglobin

LA:

Left atrium

LVEF:

Left ventricular ejection fraction

NT-ProBNP:

N-terminal pro brain natriuretric peptid

POD:

Peripheral occlusive disease

RA:

Right atrium

RAA:

Right atrial appendage

sPAP:

Systolic pulmonary artery pressure

SR:

Sinus rhythm

TAPSE:

Tricuspid annular plane systolic excursion

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Acknowledgements

We thank Johanna Lesch and Renate Wahn for contributing to these results. This publication was supported by the Open Access Publication Fund of the University of Würzburg.

Funding

This study received financial support from the Comprehensive Heart Failure Centre (CHFC) Wuerzburg.

Conflict of interest

None.

Open Access funding enabled and organized by Projekt DEAL.

Author information

Authors and Affiliations

  1. Department of Thoracic and Cardiovascular Surgery, University Hospital Wuerzburg Zentrum Operative Medizin, Oberduerrbacherstr. 6, 97080, Wuerzburg, Germany

    C. Bening, D. Keller, S. Müller-Altrock, D. Radakovic, K. Penov, M. Hassan, I. Aleksic, R. Leyh & N. Madrahimov

  2. Medical Faculty Mannheim, Center for Preventive Medicine, Heidelberg University, Digital Health Baden-Württemberg (CPD-BW), Heidelberg , Germany

    B. Genser

Authors
  1. C. Bening
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  2. B. Genser
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  3. D. Keller
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  4. S. Müller-Altrock
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  5. D. Radakovic
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  6. K. Penov
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  7. M. Hassan
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  8. I. Aleksic
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  9. R. Leyh
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  10. N. Madrahimov
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Contributions

CB: Study Design, data analysis and interpretation, manuscript writingBG: Statistical analysisDK: Patient recruitment and informationSM: Performing the experimentsDR: Manuscript editingKP: Data collection and database managementMH: Patient recruitment and information, Data collectionIA: manuscript editing and translationRL: manuscript editing and approval, data interpretation and analysisNM: manuscript editingAll authors read and approved the manuscript.

Corresponding author

Correspondence to C. Bening.

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Ethics approval

The study was approved by the Ethical committee of the University Hospital Wuerzburg, Germany (File number: 59/16-sc und 143/17-sc). Written consent of all patients included in this study is available. All methods were carried out in accordance with relevant guidelines and regulations. Informed consent was obtained from all patients and is available.

Consent for publication

Consent for publication is available from all patients.

Competing interests

The authors declare no competing interests.

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Bening, C., Genser, B., Keller, D. et al. Impact of estradiol, testosterone and their ratio on left and right auricular myofilament function in male and female patients undergoing coronary artery bypass grafting. BMC Cardiovasc Disord 23, 538 (2023). https://doi.org/10.1186/s12872-023-03582-4

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  • DOI: https://doi.org/10.1186/s12872-023-03582-4

Keywords

BMC Cardiovascular Disorders

ISSN: 1471-2261

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