Sex differences and the left ventricle: morphology matters

This editorial refers to ‘Sex-specific relationships between patterns of left ventricular remodelling and clinical outcomes’ by R.J.H. Miller et al., pp. 983--990.

It is well known that alterations in structure and function of the left ventricle are key predictors of cardiovascular disease (CVD) outcomes. Ironically, but not surprisingly, sex differences in left ventricular (LV) morphology have been better recognized and understood in health rather than in disease. For instance, both electrocardiographic and echocardiographic parameters for identifying normal vs. abnormal LV size have been defined using sex-specific criteria since the early 1980s. Acknowledging that cardiac size is not only proportionate to overall body size but also independently differs by sex, cardiac magnetic resonance imaging (cMRI) criteria have been similarly developed to provide guidance for identifying presence of LV hypertrophy (LVH) specifically for women vs. for men.¹ In the Multi-Ethnic Study of Atherosclerosis, for example, the formulas for defining LVH differ substantially for women and men: predicted LV mass = 6.82 × (height in metres)^0.561 × (weight in kilograms)^0.608 for women, compared to 8.17 × (height in metres)^0.561 × (weight in kilograms)^0.608 for men. Moreover, women demonstrate more concentric remodelling and less dilated (eccentric) hypertrophy than men, and aortic stenosis leads to sex-specific myocardial remodelling with a more concentric form of hypertrophy, less fibrosis, and better reversibility after unloading the ventricle following aortic valve replacement in women than in men.^2–5

A new report by Miller et al.⁶ adds to this literature, showing sex-specific differences in LV morphology in a large dataset of 3745 women and men who underwent both cMRI and invasive coronary angiography. The participants were stratified into four groups: (i) normal; (ii) concentric remodelling; (iii) eccentric (dilated) hypertrophy; and (iv) concentric (non-dilated) hypertrophy, then related to all-cause mortality and revascularization at 3- to 4-year follow-up. Baseline findings were consistent with prior work showing that women had more concentric remodelling, less eccentric hypertrophy, and a similar prevalence of concentric hypertrophy to men. Notably, while the all-cause mortality and revascularization prognosis was equally elevated for women and men with concentric hypertrophy, women uniquely demonstrated elevated risk with eccentric hypertrophy. Analyses exclusive to all-cause mortality were similar, suggesting that the primary contributor to the findings was cardiac mortality. While these are important novel findings, not accounting for other CVD events, such as heart attack, stroke, and heart failure, is a limitation that likely underestimates differences in major adverse cardiac events, including in those with concentric remodelling. Specifically, sex differences in LV remodelling appear to contribute to the higher prevalence of heart failure with preserved ejection fraction (HFpEF), which is more prevalent and lacks definitive therapies.⁷

Why would sex differences in LV remodelling contribute to greater adverse mortality in women and not in men? We have described in a cohort exclusively of women undergoing cMRI and invasive coronary functional testing⁸ that despite a similar LV mass and LV ejection fraction (LVEF), women with impaired myocardial perfusion reserve had greater relative wall thickness compared to women with normal myocardial perfusion reserve, a measure of coronary microvascular function. We have further demonstrated that women suffer disproportionately from coronary microvascular dysfunction,⁹ now a recognized major contributor to the rising epidemics of ischaemia with no obstructive coronary disease, and myocardial infarction with no obstructive coronary disease, and linked with elevated cardiovascular morbidity and mortality.⁹

Given that Miller et al. have confirmed that sex differences in LV remodelling have serious adverse implications, it is best to further understand the genesis in order to respond to the scientific charge of using our understanding of sex differences to improve patient outcomes. Prior sex difference studies have evaluated adult participants of convenience undergoing cardiac testing for CVD, and therefore do not inform us about biological sex differences, i.e. the mechanisms underlying sexual dimorphism in LV responses to stressors that accumulate over a life course. Of value, Goble et al.¹⁰ studied 243 11-year-old girls and boys and found that LV mass differs by sex, adjusted for weight, in healthy pre-pubertal children. Notably, they found LV mass sex difference was strongly related to body fat mass, where the girls’ lower LV mass was related to their higher fat mass. Moreover, although to a lesser extent, LV mass differences were also related to hemodynamic sex difference, where girls’ higher heart rate contributed to lower LV mass, while boys’ higher systolic blood pressure contributed to higher LV mass. Other work demonstrates that women also have higher LV elastance (systolic stiffness) than men at a given age, and steeper increases in LV elastance are seen in ageing women than men.¹¹ Although cardiomyocyte number is the same in girls and boys at birth, ageing women have a relatively attenuated decline in cardiomyocyte number and mass, with less tendency towards cardiomyocyte hypertrophy and eccentric LV remodelling compared with men.¹² It is likely that these sex differences are genetically determined by sex biases in gene expression, a consistent finding reported across organ systems and species.¹³

An unfolding body of evidence is demonstrating important sex-specific determinants of CVD. For instance: we recently reported on different lifetime trajectories in blood pressure with steeper inclines for women compared to men; others have proposed that the surplus of HFpEF in women may be an artefact relative to a sex-neutral 50% LVEF cut-off which may be relatively reduced function in women;¹⁴ and, we have also described that a sex-neutral coronary flow reserve abnormality threshold of <2.5 is less accurate for prognosis than a sex-specific threshold for women of <2.32.¹⁵ These findings underscore persistent questions regarding important measures of CVD and treatment (Table 1). Answering these and other key questions will be needed to fulfil our scientific charge. Armed with such knowledge—and an improved understanding of what the difference between the essence of a man and a woman is (Figure 1)—clinical providers and the medical establishment as a whole will be better positioned to optimize the health of each individual patient.

Table 1.

Important knowledge gaps to address regarding sex differences in cardiovascular health and disease—should women and men:

Have different blood pressure diagnosis and treatment thresholds?

Have different LVEF diagnosis and treatment thresholds?

Have different diagnosis and treatment coronary flow reserve thresholds?

Figure 1.

Funding

This work was also supported by contracts from the National Heart, Lung, and Blood Institutes nos. N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164, grants U0164829, U01 HL649141, U01 HL649241, K23HL105787, T32HL69751, R01 HL090957, R01-HL134168, R01-HL131532, R01-HL143227, R01-HL136601, and R01-HL142983, 1R03AG032631 from the National Institute on Aging, GCRC grant M01-RR00425 from the National Center for Research Resources, the National Center for Advancing Translational Sciences Grant UL1TR000124 and UL1TR001427, and from the American Heart Association (16SDG27260115), the Harry S. Moss Heart Trust, the Gustavus and Louis Pfeiffer Research Foundation, Danville, NJ, USA, the Edythe L. Broad and the Constance Austin Women’s Heart Research Fellowships, Cedars-Sinai Medical Center, Los Angeles, CA, USA, the Barbra Streisand Women’s Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles, The Linda Joy Pollin Women’s Heart Health Program, and the Erika Glazer Women’s Heart Health Project, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Conflict of interest: C.N.B.M. serves as Board of Director for iRhythm, receives personal fees paid through CSMC from Abbott Diagnostics and Sanofi. S.C. reports consulting fees, unrelated to this work, from Zogenix, Inc. All other authors report no disclosures.

The opinions expressed in this article are not necessarily those of the Editors of EHJCI, the European Heart Rhythm Association or the European Society of Cardiology.