This study characterized adaptations in cardiac morphology and function during healthy aging in women and men using quantitative CMR indices and found that age was associated with several ventricular changes in both sexes even in younger life decades. First, there was evidence of equal ventricular remodeling in women and men with increasing age, as represented by an increase in concentricity (LV mass-to-volume ratio). Second, LV stroke volume index as a determinant of cardiac output decreased with rising age in both sexes but declined stronger for men than for women. Third, in both sexes, chamber volumes decreased with age with a similar decline in RV and LV so that the volume ratio between both chambers remained constant over the adult lifetime.

Overall, the major sex-specific differences in cardiac structure and function were found to be women having generally smaller ventricular dimensions and volumes, lower left ventricular mass as well as higher biventricular ejection fractions. These results confirm many studies that have established sex-specific reference ranges for quantitative CMR parameters [24, 28, 29]. Likewise, the results of the mentioned studies demonstrated that chamber dimensions decrease with rising age. This seems to be one of the fundamental age-related physiological cardiac adaptations in both sexes. Additionally, by using RV/LV-VR for quantitative assessment, this research revealed that the size of LV and RV declined equally with age in both sexes, represented by a preserved RV/LV-VR. Thus, age as a non-modifiable risk factor may not lead to an excessive workload on a particular single ventricle and a deviation of RV/LV-VR seems to indicate a specific underlying pathology. However, there is currently only limited knowledge about the clinical relevance of RV/LV-VR in CMR. Altmayer et al. demonstrated that the use of RV/LV-VR for diagnostic assessment increases the sensitivity for detecting RV dilatation in patients with pulmonary arterial hypertension [30]. Especially in congenital heart diseases, it was shown that RV/LV-VR seems to be a sex-neutral universal measure for the assessment of RV dilatation and pulmonary regurgitation as illustrated in patients with repaired tetralogy of Fallot [31]. However, the impact of age on the development of RV/LV-VR remains unexplained. Thus, this research, to the best of our knowledge, provides the first relevant CMR insights into the age-associated progression of RV/LV-VR, implicating that this parameter could serve as an age-independent diagnostic measure.

Another essential cardiac alteration was found by an age-associated increase in concentricity (LV-MVR) in both sexes. This ventricular adaptation cannot be explained by an increase in LVM with age, but by the stronger decline of LV end-diastolic volume in relation to LVM. This adjustment reflects rather a remodeling than a hypertrophy. These results confirm the findings of the CMR study by Cheng et al. [17], who investigated age-related ventricular alterations in the large MESA cohort. The study also found that LVM only decreased slightly in the elderly in both sexes, a trend that was similarly observed in this research (insignificant between youngest and oldest age groups), although there were slight differences in the population between MESA and the cohort of this study, which included younger healthy volunteers without traditional cardiac risk factors (e.g., arterial hypertension or hyperlipidemia). These findings were also supported in the longitudinal follow-up trial of the MESA cohort by Eng et al. [32], except for a long-term increase in LVM in men, which has not been reported before. Another healthy but sex-unspecific sample was studied by Kersten et al. [16], who found that LVM and indexed LVM decreased significantly with age while LV-MVR tended to increase in the elderly (insignificantly). Nevertheless, the age-related maintaining or decreasing LVM measured in CMR studies disagrees with echocardiographic trials that reported an age-associated increase in LVM [8, 9]. Representing the currently most important routine imaging modality in cardiology, echocardiography relies on different quantification methods which may influence the quantification of LVM. It was shown that LVM was larger when measured by echocardiography compared to CMR [33,34,35].

There were no clinically relevant sex-specific differences regarding the age-associated development of the above parameters (except for greater LV-MVR and LVM in males). In that regard, these results differ from previous studies that described a higher prevalence of concentric remodeling in females [10, 13, 36, 37]. This may be attributed to a different selection of participants, including the presence of cardiac diseases or risk factors compared to the healthy sample of this research.

Further, a sex-specific difference in the age-related progression of the LV stroke volume index as a determinant of cardiac output could be found. Although there were no significant age-associated changes in LV or RV ejection fractions in both sexes, the LV stroke volume index declined, namely stronger in men compared to women. Literature confirms an age-associated decline of LV stroke volume (index) [16, 17, 32]. Remarkably, the progression of LV-SVI differed slightly depending on whether it was indexed to BSA or H, even though both indices decreased with rising age. Indexed to BSA (weight-dependent), LV-SVI decreased faster compared to LV-SVI indexed to H, especially in males. Generally, the body characteristics of this cohort were comparable to other large populational-based studies [38, 39].

The cellular composition of the ventricular myocardium could provide a possible explanation for the higher biventricular systolic performance and the lower age-related decline in LV-SVI in women. Litviňuková et al. mentioned higher proportions of ventricular cardiomyocytes in women despite an overall lower total mass compared to men [40].

Given the sex-specific crossing point of the age-correlated LV-SVI/BSA trend curves in the years of early menopause onset, one could hypothesize that women entering menopause potentially undergo specific cardiac adaptations that are caused by changes in the sex-hormonal profile. Estrogen was generally associated with numerous cardioprotective mechanisms and higher postmenopausal estrogen levels were associated with a lower risk for cardiac diseases [5, 41,42,43]. Consequently, it is surprising that especially older women with normally decreasing estrogen levels demonstrate preserved and, in some cases, higher systolic LV performance. Further sex hormones can potentially contribute to postmenopausal cardiac changes: Subramanya et al. demonstrated that an androgenic hormone pattern (higher free testosterone, lower sex hormone binding globulin levels) was connected to an increase in LVM and concentricity in postmenopausal women [44]. Future research should aim to further investigate the impact of sex-hormonal changes upon pre- and post-menopausal women regarding the cardiac morphology as well as the ventricular function. Along with the investigation of biological characteristics, the sociocultural background and social identities of patients (gender rather than sex) may also be considered in further research. The scientific and clinical assessment of sociocultural environmental factors such as gender-specific health behavior, lifestyle, physical activity, and nutrition could improve the patient care and provide relevant information about sex- and gender-specific differences in the expression and development of cardiac diseases.

Interestingly, it was shown that a regression of atrial size occurs during aging in correlation with the decrease in ventricular size observed in healthy volunteers [45]. Further, associations with age-related changes in myocardial tissue composition are known as T1-mapping times appear to increase with age, while T2-mapping times tend to decrease [46]. Women additionally demonstrated significantly higher T1-mapping times than men [46, 47]. But, published data in this regard are still conflicting. One could assume that this is related to different study cohorts and techniques. An integrated analysis of atrial and ventricular remodeling including myocardial tissue characterization as well as hemodynamic assessment could be helpful for a deeper understanding of physiological changes in the sex-specific aging heart.

This analysis was based on a retrospective and single-center design. As the identification and inclusion of healthy participants is more challenging with rising age, the participants in each age group could not be equally balanced. A comprehensive analysis of atria, parametric mapping–based myocardial tissue analysis, and phase contrast technique–based flow assessment were not possible as the data were not available in all volunteers. For ethical requirements, a contrast agent could not be applied to healthy volunteers.