Insights from physiology applied to interpretation of supranormal ejection fraction in women

Traditionally, attention has been given to cardiac enlargement, but less is known about relatively small hearts. This imbalance may result from emphasis on the Starling mechanism, relating output to extent of filling. Actually, ejection fraction (EF) follows from this relationship, where stroke volume (SV) is compared to end-diastolic volume (EDV). EF is a dimensionless number, often expressed as a percentage, and calculated from paired volume determinations, namely endsystolic volume (ESV) and EDV. A PubMed search on EF refers to >62 000 publications since 1968. In view of the popularity, it is important to inquire about the applicability and interpretation of EF. Based on the CONFIRM registry, Gebhard et al. report on excess long-term mortality in women with a hyperdynamic left ventricle (LV). Their initiative to explore both ESV and EF to characterize sexspecific subgroups is a welcome step forward. By adding insight based on physiology, our commentary addresses the connection between EF and ESV, provides the rationale for a preference in favour of ESV, and discusses energetic aspects of ‘supranormal’ EF. Keen observations by Buonanno revealed important sex-specific differences regarding LV size. This pioneer highlighted the hyperactive LV in healthy women compared to men and suggested that the combination of an increased EF and small LV volume reflects a hyperdynamic condition with increased metabolic demand. Supranormal EF as a pathological finding was probably first reported by Kahn, considering EF >85%. The entity not only occurs in disease-free women but also in patients, e.g. with phaeochromocytoma or severe anaemia, and is equivocally defined in terms of EF threshold. The distinction between the commonly encountered label ‘supranormal’ and the variant ‘high normal’ is of a trivial semantic nature, as both refer to hyperdynamic states. What has EF to do with ESV? By definition EF = 1 – (ESV/EDV). As EF depends on two components within a ratio, its interpretation involves a mathematical exercise concerning the relative impact of the numerator and denominator. In case of EF, the analytical expression which connects with ESV is remarkably simple. The use of two population-based constants permits formulation of EF as an exclusive nonlinear function of ESV. Alternatively, a convenient logarithmic approach can be applied. Both routes yield an inverse relationship. Figure 1 shows EF = SV/(ESV þ SV) for sex-dependent average SV from Gebhard et al. The non-linearity illustrates that EF increases disproportionally at smaller ESV. This finding is crucial when elucidating their results. Also, differences observed between men and women deserve close inspection. The LV is said to perform poorly at low EF values. While searching for an optimal EF, a connection has been made with the golden ratio which refers to the irrational number u, often observed in nature. The numerical value of u, 1.618, is a convenient approximation. Its reciprocal in fact comes remarkably close to a ‘normal fraction’ for EF (which depends on imaging modality used) as observed in healthy individuals. The appealing role of this number is supported by allometry, leading to similar values for healthy adults of all mammalian species. Nature appears to dictate in healthy individuals an optimal value for ESV and EDV, and hence for EF. On energetic grounds this ESV value coincides with lowest cardiac oxygen consumption. Relatively small ESV corresponds with low efficiency, much like the enormous effort required to squeeze out the last few drops of fluid from a wet sponge. The elastance concept suggests a ‘swoosh’-