Women make up almost two-thirds of HFpEF cases and have more potent risk factors than men, but assessment and modification of cardiovascular risk factors in women remain poor, a leading cardiologist says.

Presenting at CSANZ 2023 in Adelaide earlier this month, Associate Professor Clare Arnott said differences in heart failure between the sexes ranged from phenotype and pathophysiology to risk factors, prognosis and treatment response.

She pointed to estimates of between 55-63% of patients with HFpEF being women, as well as data that showed while 5% of the population older than 60 developed HFpEF, the syndrome affected 8% of women by the age of 80.

“Those numbers are really quite staggering,” said A/Prof Arnott, a cardiologist and director of the Women’s Heart Clinic at Royal Prince Alfred Hospital and head of cardiovascular program at the George Institute for Global Health, Sydney.

“There are certain differences which predispose women to a HFpEF physiology. We have different normal left ventricular (LV) geometry. So women are far more likely to have a smaller index LV volume with similar cardiac index to men.

“Females are also far more likely to have a higher systolic and diastolic LV stiffness. That seems to increase more steeply with age in women than in men.”

She said other potentially important differences included:

• Women have higher circulating naturetic peptides – and it has been purported that that means they have a greater atrial ventricular stretch.
• The male and female heart tends to respond differently to after-load stress. Females are more likely to maintain their ejection fraction but develop hypertrophy, and then, thereafter diastolic abnormalities. Men, conversely, are more likely to develop eccentric remodelling.
• Cardiomyocytes are different between the sexes and women have a lower density of β-1 adrenergic receptors.
• Women have smaller nonindexed aortic roots and they have smaller stiffer aortic arches, which leads to a higher pulse pressure, and impaired coronary flow and diastolic dysfunction.

A/Prof Arnott said women were also more likely than men to have comorbidities such as type 2 diabetes, chronic kidney disease and obesity, which played a role in the pathophysiology of HFpEF, specifically with respect to systemic microvascular inflammation, microvascular dysfunction, stiffening fibrosis and impaired LV filling.

There are also the treatment implications of comorbidities to consider.

“It’s not just about the fact that there’s a high prevalence of these risk factors, but some data suggest that they might actually be potentially more potent in women than in men,” she said.

“To give you the example of type 2 diabetes, there are data to suggest that worsening glucose tolerance has a stronger association with adverse LV remodelling and increasing wall thickness in women than in men”

Pregnancy exposures were also exclusively relevant to women and there were hormonal influences on cardiovascular disease to consider, said added.

Epicardial adipose tissue

And a “fairly exciting and new area over the last five years” is the role of epicardial adipose tissue (EAT) in the pathophysiology of HFpEF, with some data suggesting it may be more of a factor in women due to higher incidence.

“The presence of EAT is correlated not only with worse haemodynamics, but also with adverse clinical outcomes… and I think that’s a really important thing to note. I mean worsening exercise capacity, impaired myocardial structure and function, fibrosis on imaging, and impaired resting and exercise haemodynamics,” said A/Prof Arnott.

“EAT has a strong collinear relationship with generalised obesity, so it’s not entirely clear if it is independently contributing to these adverse HFpEF-related outcomes, or whether it’s just a marker of severe obesity. That’s a bit of a watch this space.”

A/Prof Arnott noted peri and postmenopausal women were a group that had higher EAT volumes and pericardial fat volumes than premenopausal women, and along with age and a greater rise in systolic blood pressure later in life compared with men, they were starting to fit together as a cohort that could be “really high risk”.

When looking at prognosis, A/Prof Arnott said some data suggested KCCQ scores were similar between women and men but there were different drivers.

In men with HFpEF, quality of life and functional capacity were most closely linked with their comorbidities and their degree of hypertrophy. In women, their quality of life and functional status were most closely linked with their age and BMI.

A/Prof Arnott said while women had a high burden of modifiable risk factors, there was poor recognition of the presence of those risk factors and poor treatment of those risk factors despite being a key recommendation in HFpEF guidelines.

She pointed to a study of 90,000 patients in GP practices in Australia showing women were 12% less likely to have a cardiovascular risk screening, let alone treatment of their risk factors.

“So the simple stuff, that multimorbidity in both sexes, but particularly in women is is really poorly done,” A/Prof Arnott said.

“We need to be treating our comorbidities, we need to be creating data that are sex disaggregated and I think that we need to be very, very conscious of those risk factors that are particularly potent in certain patients.

“There’s still a lot that we don’t know and [we need to make] a commitment as I said to further data and to be asking those important questions, but asking them in a sex-disaggregated way such that both both sexes benefit from that.”