Sex (biological factors) and gender (socio-culturally constructed norms) affect almost every aspect of cardiovascular disease. For women with heart failure, this confluence of sex and gender results in unique and significant differences from men with the same condition, from clinical presentation and management to clinical outcomes.
In the context of heart failure, generally speaking, the female sex confers protective factors. Females have a lower prevalence of atherosclerosis and a lower risk of arrhythmias. Female sex is also associated with more favorable myocardial remodeling during stress. On the other hand, woman gender confers negative factors. Heart failure in women is an understudied pathophysiology that is under-treated with guideline-directed medical therapy (GMDT). In addition, medical and device therapies are not optimized for use in women.
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Incidence and etiology of heart failure in women
The overall lifetime risk for heart failure is similar for women (20 percent) and men (21 percent). In 2020, there were 505,000 incident heart failure cases in women 55 years or older versus 495,000 in men. For all the deaths attributable to heart failure, women account for a slightly higher proportion at 52.4 percent compared to 47.6 percent for men.
Heart Failure with reduced Ejection Fraction (HFrEF) is more common in men than women; conversely, Heart Failure with preserved Ejection Fraction (HFpEF) is more common in women, occurring at about twice the rate in women – 8 to 10 percent – compared to 4 to 6 percent for men. Women have more non-ischemic cardiomyopathy, while men have more ischemic cardiomyopathy.
Certain specific etiologies of heart failure have striking sex differences. For example, Takotsubo cardiomyopathy occurs in women far more than in men with a 9:1 incidence ratio. Additionally, peripartum cardiomyopathy and breast cancer therapy-induced cardiomyopathy are heart failure etiologies unique to women.
Impact of traditional non-traditional risk factors for heart failure
“All of the traditional risk factors for heart failure – diabetes, hypertension, obesity and smoking – are more potent risk factors for the development of heart failure in women than they are in men. Obesity also puts women at higher risk of developing HFpEF,” says Aditi Nayak, MD, MS, an advanced heart failure and transplant cardiologist on the medical staff of Baylor University Medical Center, part of Baylor Scott & White Health. “This fact underscores the importance of identifying and aggressively treating these risk factors to prevent heart failure in women.”
Pregnancy is a key non-traditional risk factor for heart failure in women. Gestational diabetes is associated with a 39 percent increased risk of incident heart failure over the following seven years after the index pregnancy in adjusted models, regardless of progression to diabetes. The condition almost doubles the odds of peripartum cardiomyopathy.
Hypertensive disorders of pregnancy, such as preeclampsia and eclampsia, can present in acute heart failure. Interestingly, the associated left ventricular remodeling persists for several years post-partum. These conditions almost double the odds of HFpEF with the median time to onset after pregnancy about two and a half years.
Worldwide, peripartum cardiomyopathy is seen in 1 in 1,000 pregnancies. Although many of these patients recover within two years, there is a risk of recurrence during subsequent pregnancies.
Clinical presentation of heart failure in women
Significant differences in clinical presentation of heart failure are seen in women compared to men. Women are older at diagnosis and have more advanced symptoms when they present with the condition. Women experience more frequent orthopnea and paroxysmal nocturnal dyspnea. Women have worse functional status and quality of life, as well as more depression associated with heart failure.
“At baseline, it’s interesting to note that natriuretic peptides are actually higher in women than in men, while troponin levels are higher in men,” Dr. Nayak says. “But both biomarkers have similar diagnostic and prognostic utility.”
Pharmacokinetics and pharmacodynamics of GDMT
The pharmacokinetics and pharmacodynamics of GDMT differ in women versus men because of differences in absorption, distribution, metabolism and elimination of these drugs. This contributes to differences in dose at which maximal effect of these drugs is attained, tolerability and side effect profile.
According to Dr. Nayak, the maximum plasma concentrations of several angiotensin-converting enzyme inhibitors (ACEis), angiotensin II receptor blockers (ARBs) and beta-blockers is up to 2.5 times higher in women than men at similar doses. For women, peak benefit is reached at 50 to 60 percent of the traditional guideline-recommended target for beta blockers, with similar findings for ACEis. In contrast, risk continues to decline with up-titration of these drugs in men. Women also experience up to two times the rate of adverse events from heart failure medications compared to men.
Unique treatment considerations for women with heart failure with reduced ejection fraction
Overall, analyses of major trials have shown that GDMT for HFrEF provides comparable benefit to men and women. But because all of the foundational trials had only approximately 20 to 30 percent female representation, many of them may have been under-powered to recognize differential response to therapy. No gender-based differences were noted in the VICTORIA trial that looked at vericiguat in HFrEF or in the GALACTIC-HF trial that looked at omecamtiv mecarbil in HFrEF.
“But for those of us who use digoxin, it’s very important to remember that there were striking gender differences observed in the Digitalis Investigation Group (DIG) trial,” Dr. Nayak says. “Women who were on digoxin had a significantly higher hazard of all-cause death, but this was not noted in men. This was attributed to higher plasma concentrations of digoxin in women, even though men used higher doses in the study.”
Unique treatment considerations for women with preserved ejection fraction
Some very interesting gender-based differences have emerged in the landmark trials for HFpEF. A post-hoc analysis of the TOPCAT trial in the Americas demonstrated that spironolactone was protective for all- cause mortality in women, but did not have a significant effect on all-cause mortality in men.
A gender-specific analysis of the PARAGON-HF trial that looked at sacubitril/valsartan in HFpEF showed a lower incidence of primary end-point (heart failure hospitalizations and CV death) in women but not in men. There are no gender-based differences in SGLT2 inhibitor efficacy, and gender-based differences in GLP1 receptor agonists are still unknown.
A look at other heart failure therapies
Therapy with implantable cardioverter-defibrillators (ICDs) is associated with similar survival benefit in women and men. Conversely, cardiac resynchronization therapy (CRT) across the board is associated with better outcomes in women versus men, according to the landmark MADIT-CRT trial.
“Mechanistically, this was attributed to a higher prevalence of non-ischemic cardiomyopathy, a left bundle branch block, as well as lower QRS duration in women than in men,” Dr. Nayak says. “So, for any given QRS duration, you’re actually treating a higher level of desynchrony in women than in men when you put them on CRT. However, for unknown reasons, women are less likely to be counselled for ICD therapy, and they are less likely to receive CRT compared to men.”
Other advanced devices and procedures also offer similar benefit to both women and men. Transcatheter mitral valve repair improves outcomes regardless of gender. An implanted senor that continually measures pressure in the pulmonary artery is associated with similar reductions in pulmonary artery pressure and heart failure hospitalizations in women and men. Baroreflex activation therapy is associated with similar improvements with six-minute walk distance, quality of life and NYHA functional class in women and men.
“But when you look at atrial shunt surgery for HFpEF, very interesting gender differences start to emerge,” Dr. Nayak says. “The REDUCE LAP-HF study showed the signal of benefit in women with an incidence rate radio of .85 for the primary endpoint, while there was harm in men.”
Cardiogenic shock and advanced heart failure therapies in women
In an analysis from the Cardiogenic Shock Working Group, which included more than 5,000 patients, women were found to be more likely to present in de novo heart failure cardiogenic shock compared to their male counterparts. Women with heart failure cardiogenic shock had decreased survival at discharge and worse cardiogenic shock severity compared to men. However, in spite of that, women with heart failure cardiogenic shock were less likely to receive a heart transplant, ventricular assist device (VAD) or pulmonary artery catheter. Regardless of cardiogenic shock etiology, women had more complications in terms of vascular complications, bleeding complications and limb ischemia.
More than 50 percent of deaths from advanced heart failure occur in women. But according to UNOS and Intermacs data, women account for only 20 percent of LVAD implants and active heart transplant listings every year. The reason for this disparity is largely unknown.
How to improve these disparities for women with heart failure
“A systematic approach to improving these disparities should include sex-specific research to understand the mechanistic root cause of these disparities,” Dr. Nayak says. “We need increased female leadership in clinical trials, which will lead to increased representation of women participants in clinical trials. We need to incorporate sex differences in the early design phase of medical devices, not just perform post hoc analysis of these devices once they hit the market. Finally, we need consideration of sex-specific guidelines for GDMT and device implantation.
“As providers, we must recognize that presentation and symptom burden of heart failure are different in women,” Dr. Nayak continues. “We must recognize that women may tolerate lower doses of GDMT. They’re not just being difficult. We must understand the reasons for non-adherence to medication and clinic visits with attention to gendered social determinants of health. Give the patient the benefit of the doubt. Maybe she is taking care of an elderly parent or children at home. We should also ask about any pregnancy-related complications. If there is any doubt about the severity of illness, it is important to refer to an advanced heart failure specialist.”
