But over the past few decades, research has shown that there is another insidious offender that can silently clog arteries, increase clots and cause significant inflammation. This particle is known as lipoprotein(a), or Lp(a), and despite its significance, doctors rarely order blood tests to measure it. Some cardiologists are trying to change that.
What is lipoprotein(a)?
Lp(a) is a form of LDL, or bad, cholesterol. It is made by the liver, where an extra string of protein known as apolipoprotein(a) is attached to an LDL-like particle. “This additional protein component makes the Lp(a) particle extremely sticky — much more so than LDL particles without them,” said Robert McGarrah, a preventive cardiologist at Duke University Medical Center.
But what makes this culprit unique is that, unlike most other types of cholesterol particles, Lp(a) levels in our blood are 80 to 90 percent genetically determined. In fact, studies have found that most of us attain full expression of the LPA gene by the time we’re 2 years old, reach adultlike levels by 5 and maintain more or less the same Lp(a) levels over the course of our lifetime.
How does Lp(a) contribute to cardiovascular disease?
The structure of the Lp(a) particle allows it to generate or worsen plaque, which leads to its significant role in heart disease. “Each particle’s small size gives it the ability to readily cross cell barriers and lodge itself in the inner lining of blood vessels. The sticky part facilitates its easy aggregation and formation of plaques along vessel walls,” said Samuel Kim, a preventive cardiologist and clinical lipidologist at Weill Cornell Medicine in New York City. The sticky protein components may also interfere with the breakdown of clots and cause inflammation.
We now have unequivocal evidence that excess Lp(a) can independently cause hardening of the arteries. In fact, elevated Lp(a) increases the risk of heart attacks by 50 percent and nearly doubles the risk of having a stroke.
“It is estimated that nearly 20 to 25 percent of the world’s population has elevated Lp(a),” said Leslie Cho, section head of preventive cardiology and director of Cleveland Clinic’s Women’s Cardiovascular Center. “Measuring the levels with a simple test and identifying patients at risk for developing cardiovascular events can be critical — and even lifesaving.”
How is Lp(a) measured, and what are the target levels?
One of the biggest drawbacks to Lp(a)’s widespread clinical adoption, however, is that its measurement and target levels are not standardized.
“I have patients who’ll come in freaking out that their Lp(a) value was 40-something here and 100-something at a different lab,” Kim said. “It’s not that their levels just suddenly bumped — because that’s not how Lp(a) works — but that a different lab used a different assay and reported the results in different units.” Some labs will report Lp(a) as mass or weight in milligrams per deciliter (mg/dl). Other labs report the number of particles, or concentration, in nanomoles per liter (nmol/L).
Although we still cannot definitively say which property of Lp(a) particles is more pathogenic, recent studies might have us inching toward a consensus that the amount of Lp(a) is a better predictor of disease risk than the size of particles. The National Lipid Association’s guidelines recommend reporting Lp(a) levels as particle concentration (nmol/L), while also noting that more research is warranted.
Using that measure, by and large, most people have Lp(a) levels below 75 nmol/L. “But depending on the type of test, Lp(a) ranges can go up to approximately 10 times the upper limit of normal,” said Douglas Jacoby, medical director of the Penn Medicine Center for Preventive Cardiology and Lipid Management. There is mounting evidence that the risk of heart disease starts to rise around 75 nmol/L and spikes more steeply at levels higher than 100 nmol/L. But the debate around target levels and when to intervene is far from settled.
One reason for this discrepancy is the role of race and ethnicity. “In most racial or ethnic groups, the serum Lp(a) level is skewed toward lower values,” McGarrah said, “but African Americans and Asian Indians have a more normal distribution centered around higher mean Lp(a) levels.” There may also be Lp(a) differences due to biological sex. “For example, we do see elevated Lp(a) serum levels in women but have not seen a clear association between those higher levels and increased rates of cardiovascular disease compared to men,” said Kaavya Paruchuri, a preventive cardiologist at Massachusetts General Hospital.
How do you treat high levels of Lp(a)?
At this point, Lp(a) levels are not directly targeted for treatment. There are two main reasons: First, there are no FDA-approved medications that can appreciably reduce Lp(a) levels. Levels of Lp(a) also appear to be somewhat resistant to changes in exercise, diet and body mass index, though some of these factors are being researched.
Second, even though we have strong evidence that elevated Lp(a) levels cause cardiovascular disease, there is no evidence that the reverse association is also true, i.e., that lowering Lp(a) levels would directly reduce the frequency and extent of heart attacks and strokes.
“When we determine that a person’s Lp(a) is elevated, this suggests that they have a genetic risk for developing cardiovascular disease,” Jacoby said. Doctors then focus on reducing the risk of those events by focusing on lowering “bad” cholesterol levels. “But for people with extremely elevated Lp(a) who have already had cardiovascular events, sometimes we use a procedure called apheresis, which filters off their Lp(a).”
The limitations in therapeutic options, however, have spurred a plethora of clinical trials. One option is “something called antisense oligonucleotide therapy, which reduces Lp(a) by inhibiting the production of the protein that makes Lp(a) so sticky,” said Cho, who is co-leading Novartis’ Phase 3 Lp(a) Horizon trial at the Cleveland Clinic. In published Phase 2 trial data, this injectable medication reduced Lp(a) levels by an average of 80 percent and didn’t cause any significant safety issues.
Should you get tested for Lp(a)?
Lp(a) is not included in the routine cholesterol tests adults get at their annual physical. “It is low yield to incorporate Lp(a) in the routine cholesterol panel, because, so far, the evidence shows that the levels don’t really change over time,” McGarrah said. Instead, a doctor could specifically order an Lp(a) test during one of the visits. “It is a different test from the standard lipid panel but doesn’t require anything other than a blood draw, so it can be processed and sent with other routine tests,” he said. The cost is typically minimal for insured people.
In Europe and Canada, guidelines recommend that everyone get tested for Lp(a) at least once. This can help identify people without existing cardiovascular symptoms but with an extremely elevated level of Lp(a), which gives them a very high lifetime risk of strokes and heart attacks. Universal screening also helps identify people with less extreme Lp(a) elevations who may be at higher risk of cardiovascular events but would otherwise fall through the cracks due to normal-appearing lipid measurements.
But in the United States, the National Lipid Association does not recommend universal Lp(a) testing. Some argue that doing so is pointless, because we do not have any evidence to substantiate its benefits. Others argue that we do not have targeted treatment(s) to lower Lp(a) levels.
Instead, they recommend a more selective approach, advising testing for people who: have first-degree relatives — parents, siblings or children — with premature cardiovascular disease (especially for men who develop it before 55 years of age, and women before 65); have a personal history of early heart disease; and/or have an LDL cholesterol level greater than 190 mg/dl. Other experts also suggest testing for people ages 40 to 75 who have a borderline 10-year risk of developing cardiovascular disease based on online risk calculators.
Cardiologists, too, are on the fence about who should get screened — and when. McGarrah would like to see a one-time Lp(a) screening when people get their first routine cholesterol panel. “Whether it is [age] 18 or 25 or later, it would be good to incorporate an Lp(a) test — usually covered by insurance — to better contextualize their risk of developing cardiovascular disease,” he said. But Paruchuri thinks screening for Lp(a) is better used with patients with borderline risk. “As a patient, having an elevated Lp(a) level but no clear treatment plan could cause significant anxiety and/or increase the use of other cardiac testing unnecessarily,” she said.
Although much remains unknown about Lp(a), some experts are trying to spread awareness to allow people to better advocate for their cardiovascular health and to try to reduce the prevalence of cardiovascular disease. By some estimates, there will be a 30 percent increase in the number of people with cardiovascular disease in the next 15 years — affecting more than 130 million Americans. “There are still so many people who have never heard of Lp(a), including cardiologists, neurologists and others,” Cho said, “and we need to take active measures to change that.”
Lala Tanmoy Das is an MD-PhD student in New York City, currently doing research in molecular cardiology. Follow him on Twitter: @TanmoyDasLala