Fighting Heart Failure with Preserved Ejection Fraction in women

Men and women differ when it comes to heart failure. Aad Withaar’s research is focuses on sex-specific differences in humans and mice and the role of sex is studied in the development of heart failure with preserved ejection fraction (HFpEF).

HFpEF is a multifactorial disease accounting for a large and increasing proportion of all clinical heart failure presentations. Epidemiological evidence suggests that HFpEF is highly represented in older obese women and a so called ‘obese female HFpEF phenotype’ has been proposed. While, Heart Failure with reduced (HFrEF) is seen more in male patients. So far, no therapy has proven to improve outcomes in HFpEF, and drugs development has been hampered by the lack of animal models that adequately represent the complex human HFpEF phenotype.

Therefore, Aad Withaar and his team have developed a preclinical multifactorial HFpEF mouse model that includes advanced age, female sex, in concert with co-morbidities: elevated blood pressure, obesity and T2DM. They demonstrated that this model recapitulates the human cardiometabolic HFpEF phenotype. In this experimental animal model they evaluated two new emerging cardiometabolic drugs, that may represent a novel therapeutic target for the treatment of HFpEF.

This study was repeated in male mice -and interestingly, they observed that the development of left ventricle hypertrophy may also occur in a sex-specific manner in mice: females more often display concentric left ventricle remodeling (results in HFpEF), while males develop eccentric left ventricle remodeling, that results in HFrEF. The meaning of these differences is not fully understood yet – and these findings are currently further investigated.

Furthermore, the sex-specific content and role of different fat depots are studied in male and female animal models to better understand how obesity is as an important factor in the pathogenesis of HFpEF. This could allow for even better phenotyping of patients, and development of designer drugs or interventions targeting specific fat depots, in both men and women with HFpEF.

Together, with this pre-clinical research, Aad Withaar hopes to contribute to increasing knowledge about HFpEF in women and the role that sex-differences play in the pathogenesis of heart failure.

Aad is a PhD student with a focus on HFpEF under supervision of Laura Meems and Rudolf de Boer.

This is the seventh post in a series that highlights our projects related to sex differences in heart disease. A new post is published every two weeks.

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