After years of frequent hospital visits, Danielle Slater was given a choice: her leg or her life.
"I was like, 'Chop it off. Get rid of it', you know?" she says.
"I had six or seven surgeries in a span of seven months. The first one was under the knee, and then it just kept going, chopping a bit more off."
The 50-year-old, from Ryde in Sydney’s north, has gradually had her right leg amputated over the past three years, after developing peripheral artery disease and heart issues.
Peripheral artery disease, known as PAD for short, is the blockage or narrowing of vessels in the legs which carry blood from the heart.
PAD is not immediately life threatening, but those with the condition are up to six times more likely to have a heart attack or stroke.
It can also restrict blood flow to the limbs, and in Australia, one person with diabetic-related foot disease will have an arm or leg amputated every three hours due to the disease.
The rate in people who don't have diabetes varies, but experts say it is still high, with one study of 186 people estimating it accounted for 18 per cent of cases.
While PAD has historically affected men, researchers say there's been an increase in the prevalence in women, who also face challenges getting a diagnosis due to a tendency to present with atypical symptoms.
But they hope ongoing research — including the analysis of tissue samples from patients undergoing amputation — will help them understand the differences in how the disease presents in men and women, and to develop strategies to better target treatments.
What causes peripheral artery disease?
Peripheral artery disease develops when plaques that are made up of fat, cholesterol and other substances build up in the walls of the arteries, usually in the legs or feet.
Things like ageing, a family history of the disease, diabetes, hypertension, high cholesterol and smoking all increase the risk of this occurring.
These plaques can harden, which narrow the opening of the arteries and restrict blood flow, or they can break open, which leads to a blood clot.
For Danielle, the first signs of trouble came in the form of aching legs and a pain in her calves that would kick in when she got home for the day.
She noticed the problem about a year after having abdominal surgery following her recovery from stage 4 uterine cancer.
"That's when the blood clots started coming down my legs," Danielle says.
"It was three years of coming into hospital every two to two-and-a-half months, and then that's when doctors said to me, 'Right, you've got to make a decision — your leg is dying, what do you want to do?'"
Peripheral artery disease is thought to affect about one in five adults and about 20 per cent of those aged over 70, with men making up the majority of hospitalisations and deaths in Australia.
But there's currently no national screening for the condition, which means the prevalence of the disease among men and women isn't fully known.
Prompted by long-running suspicions that PAD is being under-reported in women, a team of researchers led by Mary Kavurma, an associate professor at the Heart Research Institute, trawled through medical databases to review gender inequalities.
The condition is a "silent killer," Dr Kavurma says.
"Everyone knows all about heart attack and stroke, but ... people aren't aware of the symptoms of PAD and its risks.
"It doesn't help that 50 per cent of patients, the majority of these being women, do not have the typical signs or symptoms, which makes diagnosis difficult," she says.
When it comes to symptoms, it's not always 'clear cut'
While historical studies have contributed to the idea that the disease predominantly affects men, the research group's report — published in the European Heart Journal — found that more recent international epidemiological studies reported women to have at least a similar, if not higher, prevalence than men.
Pointing to a 2019 paper, which found a higher prevalence for PAD in women over the age of 25 in high-income countries, Dr Kavurma says the disease is likely being under-reported.
It's a multi-faceted problem with no simple explanation, but researchers believe some of these gaps in information stem from wider challenges around screening and health literacy.
The presentation of peripheral artery disease was once thought to be "very clear cut", with doctors relying on symptoms like sore legs and pain when walking, to identify the condition, says Jon Golledge, director of the Queensland Research Centre for Peripheral Vascular Disease and co-author of the review.
But international research has found that patients often present without these "classic symptoms", and often have a range of atypical symptoms, such as pain in other areas of the body, or may be completely asymptomatic.
"So there's a range of presentations and simply relying on the patient's symptoms is not a good way to diagnose peripheral artery disease," Professor Golledge says.
Studies have shown women can experience symptoms that feel more like fatigue or heavy legs, adds Viv Chuter, a professor of podiatry at Western Sydney University.
It means clinicians may not immediately flag that it's the result of problems with blood flow, which can lead to under-diagnosis of the condition.
Pointing to an overall lack of awareness of the condition among the public and health providers, Dr Kavurma says women "don't always listen to their bodies" and are more likely to attribute symptoms like sore legs to "having a busy life".
"They're busy dealing with the kids, they're busy running after the dog, they're busy at work, they're just on their feet all the time," she says.
"They don't think that perhaps 'I've got pain in my calves, maybe it could be more than just me being busy.'"
The differences could be more complex than we realised
Peripheral artery disease can also develop, present and progress differently in men and women due to changes in disease biology and lifestyle factors.
Risk factors like diabetes and high cholesterol are more likely to result in peripheral artery disease developing for women than for men, while women have been shown to be less responsive to some of the lifestyle interventions traditionally used to tread PAD like physical activity, says Professor Chuter.
"So these things are all contributing to higher rates in females."
Researchers are looking inside the body to try and understand how the disease mechanisms may vary between men and women, although Dr Kavurma cautions that the information is very limited because we "just don't have a great understanding" of it.
While PAD has been traditionally viewed as a "large vessel disease" (which means the larger arteries are blocked), researchers are now learning that tiny blood vessels known as the microvasculature, which average less than 0.3 millimetres in diameter, also play a role.
"[PAD] is almost analogous to coronary microvascular dysfunction in women," Dr Kavurma says.
"That is a function of the small arteries surrounding the heart, and has only just been recognised to be a problem, particularly in women.
"Why are women asymptomatic? Is it because the disease is different and maybe it's acting on the microvasculature rather than the large vessel?"
To better understand how the disease presents and responds to treatment, the Heart Research Institute — alongside vascular surgeons from Concord Hospital and Royal Prince Alfred Hospital — are collecting tissue samples from patients that are undergoing amputation.
It means they can analyse things like blood vessels from the limb tissue to look at how they react, relax and dilate, and respond to different drugs.
"We are looking at everything under the sun," Dr Kavurma says.
That includes using "cutting-edge technologies" to look closely inside the cells to determine if there any changes at a molecular or genetic level.
Increased risk of heart attack and stroke 'what people don't understand'
If the research team does find molecules and proteins that are altered, they hope to use "new strategies to target those in a personalised way", Dr Kavurma says.
But there are also a number of modifiable risk factors that can be addressed to reduce the risk of peripheral artery disease occurring or worsening.
Clinical trials aimed at implementing better methods of controlling these risk factors in a way that's "equitable to people" are currently underway, notes Professor Golledge.
Pointing to the Queensland Research Centre for Peripheral Vascular Disease's telehealth clinical trial in Townsville, he says holistic approaches like connecting patients with an endocrinologist and exercise program have been shown "to be beneficial for people with this problem for a number of reasons".
Above all, Danielle hopes others will learn the warning signs of the disease and avoid "shrugging off" concerns.
Though her diagnosis has had a profound impact on her life, she considers herself lucky that the blood clots were in her legs, not her brain or heart.
"If it was the other way around, I would have either had a heart attack or a stroke," she says.
"This is what people don't understand and why people need to get it sorted out."
