Sex Matters: A Comprehensive Comparison of Female and Male Hearts

Abstract

Cardiovascular disease in women remains under-diagnosed and under-treated. Recent studies suggest that this is caused, at least in part, by the lack of sex-specific diagnostic criteria. While it is widely recognized that the female heart is smaller than the male heart, it has long been ignored that it also has a different microstructural architecture. This has severe implications on a multitude of cardiac parameters. Here, we systematically review and compare geometric, functional, and structural parameters of female and male hearts, both in the healthy population and in athletes. Our study finds that, compared to the male heart, the female heart has a larger ejection fraction and beats at a faster rate but generates a smaller cardiac output. It has a lower blood pressure but produces universally larger contractile strains. Critically, allometric scaling, e.g., by lean body mass, reduces but does not completely eliminate the sex differences between female and male hearts. Our results suggest that the sex differences in cardiac form and function are too complex to be ignored: the female heart is not just a small version of the male heart. When using similar diagnostic criteria for female and male hearts, cardiac disease in women is frequently overlooked by routine exams, and it is diagnosed later and with more severe symptoms than in men. Clearly, there is an urgent need to better understand the female heart and design sex-specific diagnostic criteria that will allow us to diagnose cardiac disease in women equally as early, robustly, and reliably as in men.

Systematic review registration: https://livingmatter.stanford.edu/.

Keywords: athlete's heart; cardiac remodeling; concentric hypertrophy; dilated cardiomyopathy; eccentric hypertrophy; hypertrophic cardiomyopathy; sex differences; sex-specific diagnostics.

Figure 1

Sex differences in the healthy human heart across life. At birth, the female heart is +5% larger than the male heart (Altman and Dittmer, 1962); during adulthood, the female heart becomes −26% smaller than the male heart (Molina and DiMaio, 2012, 2015); in the elderly, differences become less pronounced and the female heart is −4% smaller than the male heart (Sheikhazadi et al., 2010). Mouse (Slawson et al., 1998) and whale (Race et al., 1959) hearts are shown for comparison.

Figure 2

Sex differences in healthy heart size. The whole-heart view compares an average male human heart (Zygote Media Group Inc., 2014), shown in red, to an isometrically scaled down female heart, which is −26% smaller in mass. Based on isometric scaling, the female ventricular wall thickness and its ventricular and atrial diameters would be −9.0% smaller than their male counterparts.

Figure 3

Physiological adaptation in endurance and resistance athletes. According to Morganroth's hypothesis, endurance athletes tend to develop eccentric hypertrophy associated with ventricular dilation caused by volume overload, while the wall thickness remains relatively constant. Resistance athletes tend to develop concentric hypertrophy associated with ventricular wall thickening caused by pressure overload, while the chamber size remains relatively constant.

Figure 4

Physiological adaptation to volume and pressure overload. Volume overload induced by endurance training causes primarily eccentric growth associated with ventricular dilation, while pressure overload induced by resistance training causes primarily concentric growth associated with ventricular wall thickening. Simulations allow us to probe the effects of endurance and resistance training on muscle fiber length and thickness and on the geometry of the heart as a whole. Blue colors indicate the baseline fiber length and thickness; yellow colors indicate a fiber lengthening and thickening of up to 40%.

Figure 5

Physiological adaptation to dynamic and static exercise and training duration and intensity. According to Mitchell's classifications, left, dynamic exercise is associated with an increase in cardiac output, while static exercise is associated with an increase in blood pressure. According to Beaudry's classifications, right, the degree of cardiac adaptation depends on the duration and intensity of training.

Figure 6

Sex differences in short-term fiber stretch and elastic response. Simulated short-term fiber stretch for male and female hearts, left and right, subject to the stroke volumes of healthy and athlete's hearts, top and bottom. In the healthy heart, simulated fiber stretches remain well within the physiological regime of 1.10 to 1.15, with a few local peaks on the order of 1.20. In the athlete's heart, simulated fiber stretches would exceed the physiological regime and reach values of 1.20 to 1.30, with almost the entire heart experiencing stretches above 1.20. Volume overload on the whole heart level induces an overstretch on the cellular level and triggers physiological adaptation in the athlete's heart. Male and female hearts respond similarly under both healthy and athletic conditions.

Figure 7

Sex differences in long-term fiber lengthening and adaptive growth. Simulated long-term fiber stretch for male and female hearts, left and right, subject to the stroke volumes of healthy and athlete's hearts, top and bottom. In the healthy heart, fiber stretches remain well within the physiological regime of 1.10 to 1.15, with a few local peaks on the order of 1.20. In the athlete's heart, chronically elevated fiber stretches trigger a chronic fiber lengthening of up to 1.50. Volume overload on the whole heart level induces an overstretch on the cellular level and triggers physiological adaptation in the athlete's heart. Male and female hearts respond similarly under both healthy and athletic conditions.

Figure 8

Differentiating physiological from pathological adaptation. Wall thickness and cavity size are diagnostic criteria for which a subset of physiologically remodeled athlete's hearts overlaps with pathologically remodeled dilated and hypertrophic cardiomyopathy hearts, left. Relative wall thickness and sex-specific left ventricular mass are criteria which differentiate normal geometry from hypertrophic, even in the case of extreme athletic adaptation, right.