Sex Differences in Cardiac and Clinical Phenotypes and Their Relation to Outcomes in Patients with Heart Failure

Abstract

Biological sex is one of the major factors characterizing the heart failure (HF) patient phenotype. Understanding sex-related differences in HF is crucial to implement personalized care for HF patients with various phenotypes. There are sex differences in left ventricular (LV) remodeling patterns in the HF setting, namely, more likely concentric remodeling and diastolic dysfunction in women and eccentric remodeling and systolic dysfunction in men. Recently supra-normal EF (snLVEF) has been recognized as a risk of worse outcome. This pathology might be more relevant in female patients. The possible mechanism may be through coronary microvascular dysfunction and sympathetic nerve overactivation from the findings of previous studies. Further, estrogen deficit might play a significant role in this pathophysiology. The sex difference in body composition may also be related to the difference in LV remodeling and outcome. Lower implementation in guideline-directed medical therapy (GDMT) in female HFrEF patients might also be one of the factors related to sex differences in relation to outcomes. In this review, we will discuss the sex differences in cardiac and clinical phenotypes and their relation to outcomes in HF patients and further discuss how to provide appropriate treatment strategies for female patients.

Keywords: guideline-directed medical therapy; heart failure; sex difference; supra-normal EF.

Figure 1

The proposed mechanisms mediating worse outcome by snEF in women. The snEF might reflect LV stiffening rather than enhanced systolic function (see the Discussion). Small LV size was also shown to be associated with LV stiffness. Small LV size can cause lower cardiac output and elevated LV filling pressure, which can lead to sympathetic nerve activation. Microvascular dysfunction and sympathetic nerve activation are shown to be associated with snEF, exclusively in women. Since estrogen is shown to attenuate sympathetic nervous tone and favorably regulate coronary microcirculation, especially women after menopause might be more susceptible to these pathologies. These could explain the worse outcomes of female patients with snEF. LVEF, left ventricular ejection fraction; snEF, supra-normal left ventricular ejection fraction.