Hearts apart: sex differences in cardiac remodeling in health and disease
Thomas G. Martin, Leslie A. Leinwand
Thomas G. Martin, Leslie A. Leinwand
Published July 1, 2024
Citation Information: J Clin Invest. 2024;134(13):e180074. https://doi.org/10.1172/JCI180074.
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Hearts apart: sex differences in cardiac remodeling in health and disease

Abstract

Biological sex is an important modifier of physiology and influences pathobiology in many diseases. While heart disease is the number one cause of death worldwide in both men and women, sex differences exist at the organ and cellular scales, affecting clinical presentation, diagnosis, and treatment. In this Review, we highlight baseline sex differences in cardiac structure, function, and cellular signaling and discuss the contribution of sex hormones and chromosomes to these characteristics. The heart is a remarkably plastic organ and rapidly responds to physiological and pathological cues by modifying form and function. The nature and extent of cardiac remodeling in response to these stimuli are often dependent on biological sex. We discuss organ- and molecular-level sex differences in adaptive physiological remodeling and pathological cardiac remodeling from pressure and volume overload, ischemia, and genetic heart disease. Finally, we offer a perspective on key future directions for research into cardiac sex differences.

Authors

Thomas G. Martin, Leslie A. Leinwand

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Figure 4

Cellular signaling associated with exercise-induced cardiac hypertrophy in female mice.

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Cellular signaling associated with exercise-induced cardiac hypertrophy ...
Cardiac hypertrophy with exercise is pronounced in female mice compared with males. At the cellular level, female mice display increased Akt activation, which regulates protein synthesis through modulation of mTOR and GSK3β. Female hearts also display activation of factors in MAPK signaling cascade, including P38 and ERK, which indirectly control transcription of a hypertrophic gene program via direct modulation of various transcription factors (Tx). The female mouse heart also has increased expression of nuclear factor erythroid 2–related factors 1 and 2 (NRF1 and NRF2) after exercise. NRFs translocate to the nucleus in response to oxidative stress from ROS and upregulate expression of antioxidant factors, including SOD1 and SOD2. Factors in pink have been directly shown to be induced with exercise; factors in gray are implicated based on the pathways activated.