Disclosures: Gulati and Lala report no relevant financial disclosures.
December 08, 2021
4 min read

Sex differences in HF: Risk factors, presentation, knowledge gaps vary between women, men

Disclosures: Gulati and Lala report no relevant financial disclosures.
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A new review in the Journal of Cardiac Failure highlights differences between women and men in HF risk factors, pathophysiology, treatment and more.

Healio spoke with co-authors Anu Lala, MD, assistant professor of medicine (cardiology) at Icahn School of Medicine at Mount Sinai, and Martha Gulati, MD, MS, FACC, FAHA, president elect of the American Society for Preventive Cardiology, about the review and what actions must be taken to improve the diagnosis, care and prevention of HF in women.

Graphical depiction of source quote presented in the article
Anu Lala, MD, assistant professor of medicine (cardiology) at Icahn School of Medicine at Mount Sinai.

Healio: What are some of the most significant pathophysiological differences in the presentation of HF between women and men?

Lala: Traditional risk factors for HF, including hypertension, diabetes and smoking, may be less prevalent in women compared with men, but when present portend a higher risk for HF in women compared with men. Obesity happens to be more prevalent among women and is also associated with higher risk of HF in women, particularly HF with preserved EF (HFpEF), mediated at least in part by excess adipose tissue-derived signaling molecules, including neprilysin and aldosterone.

Healio: Why do women tend to present with more severe HF disease compared with men?

Lala: This remains a gap in knowledge and any reasons presented remain speculative. It could be that women ignore symptoms more frequently until they are severe. It could also be that gender-neutral thresholds for EF and QRS duration, for example, limit therapies to only a subpopulation of women who would actually derive benefit.

Martha Gulati

Gulati: As a result of our overt focus on EF — which, if women start off with a higher “normal” EF, when it decreases we may not even recognize it as HF — we have likely undertreated and under-identified women with HF. Repeat hospitalization with HF symptoms and “normal EF” occurs frequently before even a diagnosis of HpEF happens. Additionally, there is a difference in how we treat traditional risk factors that ultimately can affect the development of HF. Undertreatment of hypertension, common in women, can result in increasing the progression of HF. HF can be preventable, but it requires us seeing this as a disease in women.

Healio: What risk factors most strongly predispose women to HF?

Lala: In addition to traditional risk factors noted previously, there are sex-specific risk factors that may lend predilection for HF, including pregnancy-associated complications such as eclampsia. Breast cancer-related treatments, specific responses to stressors — as in stress cardiomyopathy, most commonly encountered among women — and a greater prevalence of autoimmune diseases such as lupus also may contribute to development of HF.

Gulati: Uniquely for women also is the role of pregnancy on HF. Peripartum cardiomyopathy occurs in women. The risk for preeclampsia also increases the risk for HF. One traditional risk factor that is underappreciated in terms of its risk for CAD and also HF is diabetes, and this risk is greater in women compared with men, not only in terms of its prevalence but its association with the risk for HF. We now have many novel medications for the treatment of diabetes that can reduce the risk for HF. Let’s hope, as we start using them, that we do not find disparities in their use in women who are more susceptible to the risk for developing HF as a result of diabetes.

Healio: Can sex-based cutoffs for LVEF be revaluated to optimize care?

Lala: This is a hot topic in our field right now. The benefits of SGLT2 inhibitors across the EF spectrum in addition to mineralocorticoid receptor antagonists and sacubitril/valsartan (Entresto, Novartis) in some populations have prompted a questioning of whether resting indication for therapy based on EF is valid. Though more work is needed to fully answer that question and going further as to whether sex-specific thresholds for EF should be considered, my personal approach is moving toward a treatment with guideline-directed medical therapy across the EF spectrum.

Gulati: Sex-specific thresholds for biomarkers also remain an area of interest. Brain natriuretic peptide (BNP) levels in health are higher in women compared with men. But to date, we do not have sex-specific thresholds for this biomarker in HF. It seems that in HF, women either have no difference in BNP levels or lower levels perhaps because men have more HFrEF and higher BNP as a result.

Healio: What are the biggest gaps in care for women at risk for/with HF?

Lala: Our Journal of Cardiac Failure paper outlines many of them. Perhaps one of the most pressing gaps is better understanding the pathophysiology of HFpEF in women compared with men.

Healio: What challenges remain to improve HF diagnosis and treatment in women?

Lala: There are likely many factors, including but not limited to the fact that women are underrepresented in clinical studies, in the cardiology workforce, and underrepresented in clinical trial and study leadership.

Gulati: Agreed. The biggest gap is the lack of inclusion of women in clinical trials of HF. Of all CVD states, HF continues to enroll the least women. We need to ensure that investigators, pharmaceutical companies, and the NIH and FDA insist on enrollment of women in clinical trials, particularly in HF.

Healio: What immediate steps can be taken to move the needle on HF care for women?

Lala: The steps that are most readily tangible are a greater number of sex-based analyses of clinical trials and increased inclusion of women in clinical studies as patients but also among leadership of these studies.

Gulati: One, use evidence-based guidelines equally in men and women. Two, get more women into HF trials. Three, increase the awareness of how specific HF drugs work differently in women compared to men. Four, we need to consider sex-specific guidelines for the treatment of HF or specific recommendations for women where there are sex differences identified. Five, increase funding for research in identifying sex difference in the prevention and treatment of HF.

Healio: Any final comments?

Lala: I think the way we communicate disease — in this case, HF — matters, potentially even more so for women. For instance, the diagnosis of HF is devastating. If we as clinicians can shift our framework to speak about function and not failure, we may stand to have more patient engagement, awareness and empowerment. How such a change may influence practice patterns and outcomes remains to be seen.

For more information:

Anu Lala, MD, can be reached at anu.lala@mountsinai.org; Twitter: @dranulala.

Martha Gulati, MD, MS, FACC, FAHA, can be reached at martha.gulati@gmail.com; Twitter: @DrMarthaGulati.