Effects of biological sex on the pathophysiology of the heart

Abstract

Cardiovascular diseases are the leading causes of death in men and women in industrialized countries. While the effects of biological sex on cardiovascular pathophysiology have long been known, the sex-specific mechanisms mediating these processes have been further elucidated over recent years. This review aims at analysing the sex-based differences in cardiac structure and function in adult mammals, and the sex-based differences in the main molecular mechanisms involved in the response of the heart to pathological situations. It emerged from this review that the sex-based difference is a variable that should be dealt with, not only in basic science or clinical research, but also with regards to therapeutic approaches.

Keywords: cardiac failure; gender; heart; hypertrophy.

Figure 1

Summary of the effects of oestrogens, according to the cell types in the heart, which can be involved in cardioprotection induced by oestrogens.

Figure 2

Molecular mechanisms of oestrogen action in cardiac cells, such as endothelial cells. Oestrogens can bind and activate the ERs, thereby inducing intracellular signalling cascades. Additionally, oestrogens influence other signalling pathways in the heart: oestrogens activate (i) the PI3K/Akt pathway, (ii) the Gq-coupled receptors, which results in the production of inositol trisphosphate (IP3) and the subsequent triggering of intracellular Ca²⁺ release and NO production, and (iii) the PKC/MAPK signal transduction pathways. All these signalling pathways are triggered at the level of the plasma membrane and activate intracellular cascades that converge to cytosolic targets and transcription factors and cofactors modulating gene expression. Finally, oestrogens can bind to mitochondria-specific receptors, through an increase in nuclear transcription of the nuclear respiratory factors (NRFs). MEK, mitogen-activated extracellular signal-regulated protein kinase; RAF, rapidly accelerated fibrosarcoma; ROS, reactive oxygen species.

Figure 3

Heart failure as the underlying cause of death. The analysis clearly demonstrated that during the last decade, the age-standardized death rate per 100 000 inhabitants was unrelated to sex differences in seven European countries (reprinted from Laribi et al., with permission).