Measuring the levels of three biomarkers in blood in midlife may give women a clearer picture of their risk of major cardiovascular events like heart attacks and strokes decades earlier than current risk calculators do, a new study suggests.
When it comes to the worries that women have about their health, heart disease isn’t usually at the top of the list – but it probably should be.
Heart disease is the No. 1 killer of women in the United States. In 2021, it was responsible for the deaths of more than 310,000 women, about 1 in every 5 female deaths, according to the US Centers for Disease Control and Prevention. About 80% of women ages 40 to 60 are living with at least one risk factor for coronary artery disease, research has found, but only about half of women recognize heart disease as their biggest health risk.
Experts say that having better measures of risk earlier in life might help women take critical steps to improve their health before it’s too late.
Common tests give a new look at heart risk
The tests highlighted in the study are not new. “These are widely available. It’s nothing more than checking off a box with a lab slip,” said study author Dr. Paul Ridker, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital. They are also inexpensive, he says, ranging from $10 to $12 per test.
The study found that these three test results, considered together, could predict cardiovascular risk in seemingly healthy women as much as 30 years before a major cardiovascular event like a heart attack or stroke, a finding that Ridker said was astonishing.
“The fact that it works in primary prevention is mind-blowing to me, because it’s telling us that the process that’s driving atherosclerotic disease in these young women is there very early in life,” he said.
For the study, which was published Saturday in the New England Journal of Medicine and presented at the European Society of Cardiology conference in London, Ridker and his colleagues followed nearly 40,000 women for 30 years starting in the early 1990s. The research was funded by the US National Institutes of Health.
The study participants were health professionals who were invited to enroll. Their average age at the beginning of the study was 55, but some were as young as 40. One in four had high blood pressure, and about 1 in 8 were current smokers. Nearly 3% had a history of diabetes, and about 14% had at least one parent who’d had a heart attack before the age of 65.
At the start of the study, about 28,000 women agreed to provide blood samples. The researchers used these to measure three biomarkers: low-density lipoprotein, or LDL, commonly known as bad cholesterol; high-sensitivity C-reactive protein, or CRP; and lipoprotein(a), or LP(a).
Igniting a ‘biologic explosion’
These three factors each influence cardiovascular risk in different ways.
LDL cholesterol contributes to fatty buildup in the arteries and has long been a classic measure of heart risk.
High-sensitivity CRP is newer. It’s part of the immune system’s response to cholesterol, and it’s a way for researchers to measure simmering inflammation in blood vessels, the kind a person wouldn’t be able to feel.
When cholesterol starts to build up in the arteries, it forms crystals. The immune system sees the crystals as foreign and starts to mount a response to clear them away. In the process, high-sensitivity CRP is made.
LP(a) – pronounced LP-little-a – is a lipid that can accumulate in blood vessels and form artery-clogging plaques, similar to LDL cholesterol. A person’s risk for a high LP(a) level is largely inherited. About 1 in 5 people worldwide has a high LP(a) level but may not know it because they wouldn’t have any symptoms. A person can live a healthy lifestyle, have normal cholesterol and still develop a major artery blockage because of LP(a).
In the clinic, doctors consider and measure each of these biomarkers independently. “But they’re not independent of each other in terms of biologic explosion that they ignite,” Ridker said.
That’s a major strength of this study, said Dr. Leslie Cho, director of the Women’s Cardiovascular Center at the Cleveland Clinic.
“It’s the additive effect of the risk factors that are very interesting and incredibly potent,” said Cho, who was not involved in the research.
More elevated markers means greater risk
At the end of the study period, researchers looked to see how many of the participants had had a major cardiovascular event: a heart attack, stroke, a procedure to open an artery near the heart or death from a cardiovascular event. The women in the study experienced roughly 3,600 first major cardiovascular events.
The researchers then divided the participants into five roughly equal parts called quintiles, according to their levels of each biomarker, and compared the risk of major cardiovascular events among those in the highest quintile against those in the lowest.
They found that the three biomarkers were each individually associated with an increased risk of cardiovascular disease, with inflammation appearing to be the strongest driver.
Women with the highest levels of high-sensitivity CRP – over 5.18 milligrams per liter – were about 70% more likely to have a major heart event than those in the lowest level. Women with the highest levels of LDL – over about 151 milligrams per deciliter – had a 36% higher risk of a major heart event. And women with the highest levels of LP(a) – over 44 milligrams per deciliter – had a 33% greater risk of a major cardiovascular event.
The effects were even stronger when the three biomarkers were considered together. Compared with women who didn’t have high levels of any of these three biomarkers, those who had high levels of all three were nearly three times more likely to have a major heart event and nearly four times more likely to have a stroke.
“We continue to underdiagnose and undertreat women compared to men,” Ridker said, adding that one of the key messages of the study is that middle-age women with elevated risks should be identified and treated earlier.
“Why are we starting statins in women at age 65 when we start them in men at age 50? Right? I mean, it’s just biologically silly,” Ridker said.
Getting doctors to test
The study suggests that doctors should be checking these markers as a routine part of primary care, but many don’t, said Dr. Gina Lundberg, a preventive cardiologist who is clinical director of the Women’s Heart Center at Emory University.
“A lot of physicians never draw the c-reactive protein or the LP(a) levels, so they’re missing out on this information,” said Lundberg, who was not involved in the study.
Ridker said he hoped the study would educate doctors about the importance of ordering these tests. “I would personally like to see universal screening for these three things,” he said.
There are medications to lower LDL cholesterol and to help control inflammation, including low-dose colchicine, a drug that’s traditionally been used to treat gout. But no drugs are specifically approved to lower LP(a), although several are being tested.
Independent experts said the new study was significant because most risk calculators tend to underestimate heart risks for women.
“It’s always been very difficult to assess heart disease risk in women because women tend to get heart disease later in life. A lot of the traditional risk factors that we use – the main one that we use is American Heart Association calculator – tends to underestimate the lifetime risk for women,” said Dr. Sonia Tolani, co-director of the Columbia Women’s Heart Center.
The study has some important limitations, too. Nearly all the women who took part in the study were White. Because they were health professionals themselves, they had better-than-average access to health care and health information and were healthier in many respects than women in the general population.
“Is it applicable to women in different socioeconomic spectrums? And is it going to be expandable to minority women?” Tolani asked of the study findings.
African Americans and South Asian women tend to have higher LPL(a) levels than Whites, Tolani noted, so that part of the study may not apply to them.
“I think that’s the biggest flaw I see,” she said.
On the other hand, the particular risk factors for heart disease in women have long been ignored, so this study is a milestone in that sense.
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“We don’t have a lot of studies done in women, in cardiology, or frankly in much of medicine, so it is good to have a study focused on women and looking at their risk,” said Dr. Anum Minhas, director of Cardio-Obstetrics at the Johns Hopkins School of Medicine.
“Looking 30 years early of course you’re going to have the strongest chance of preventing even those risk factors leading to heart disease,” said Minhas, who was not involved in the research.
Even though all three biomarkers are well-known to cardiologists, the high-sensitivity CRP and the LP(a) test aren’t measured or used much in primary care, which is where doctors might first screen patients.
For people who might want to get the results of these tests at their next checkup, Ridker suggests that it might be smart to come prepared.
“You might want to bring the paper with you,” he said.