Advancing our recognition of sex differences among individuals with transthyretin amyloid cardiomyopathy (ATTR-CM) can foster more effective, personalized management strategies for both women and men with the disorder, according to findings from a review published recently in Heart Failure Reviews.

Emerging evidence suggests that sex differences may play a key role in the clinical manifestations, outcomes, and progression of disease in patients with ATTR-CM. It is hoped that examining sex variations in individuals with ATTR-CM may help to improve our current understanding of the condition, as well as provide insights into the development of sex-specific, tailored management approaches for treatment of the disorder.

The researchers of the current analysis sought to summarize the current literature regarding sex differences among patients with ATTR-CM. Their review explores epidemiologic features of the disease in which the incidence, prevalence, and age at onset in females and males have been evaluated.

ATTR-CM can be hereditary in nature or due to amyloid deposition that is derived from wild-type transthyretin (TTR). Both types of ATTR-CM affect mainly men. In fact, among men, disease prevalence increases with age, with more than 80% of all diagnosed cases reported in males. This difference in prevalence may be associated with a variety of factors, such as genetic issues, environmental causes, and diagnosis bias, including the lack of sex-specific cutoffs or the use of nonindexed considerations.

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Although women are affected less by ATTR-CM, their age at diagnosis is generally older than that of men. Moreover, women usually present with a history of heart failure with preserved ejection fraction and/or carpal tunnel syndrome. In addition, premenopausal women with the disorder may have a particular level of myocardial protection.

Genetic factors appear to play a critical role in the development and subsequent progression of ATTR-CM, with pathogenic mutations in the TTR gene recognized as being responsible for hereditary types of the disorder. Of note, “certain mutations exhibit sex-specific penetrance and phenotypic variations.”

Further, sex hormones, including testosterone and estrogen, have been shown to modulate cardiovascular pathology and physiology among those with ATTR-CM. Studies have demonstrated that estrogen can exert a protective effect on the cardiovascular system, including anti-inflammatory, vasodilator, and antioxidant properties.  

Amyloid plaques comprise a number of different proteins, with sex differences in their composition being observed. In addition, the immune system is known to play a key role in the pathogenesis of ATTR-CM, with immune cell activation and inflammatory processes promoting myocardial damage and fibrosis. Sex-based differences in inflammatory signaling and immune responses may impact disease progression, with females typically exhibiting more robust immune responses with a greater antibody response compared with males.

“Understanding the impact of sex differences in ATTR-CM is of paramount importance for accurate diagnosis and management of this condition,” the researchers emphasized. “Efforts should be therefore made to promote inclusion of women in clinical trials, ensuring adequate representation and allowing for sex-specific analysis,” they concluded.


Aimo A, Panichella G, Garofalo M, et al. Sex differences in transthyretin cardiac amyloidosis. Heart Fail Rev. Published online August 11, 2023. doi:10.1007/s10741-023-10339-w