The amount of cholesterol that HDL particles carry, commonly reported on blood tests, doesn’t appear to be the most important detail when it comes to heart health.
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“Good” and “bad” cholesterol: These well-known characters have long starred in the saga of heart health. But in a major plot twist, “good” cholesterol, it turns out, is not always so good.
In the last dozen years or so, research on the particles that carry so-called good cholesterol — known as high-density lipoprotein, or HDL — has presented a much more nuanced and conflicted story about HDL’s effect on cardiovascular disease.
And a new, large study brings fresh doubt. High levels of HDL cholesterol were not associated with protection against heart disease in Black or white participants, researchers reported in the November Journal of the American College of Cardiology. For low levels of HDL cholesterol, there was a split, with a link to higher risk of heart disease in white participants but not in Black participants.
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The study is the first to find a difference in the risk tied to low levels of HDL cholesterol between Black and white people. It also adds to accumulating evidence that a high level of HDL cholesterol isn’t necessarily helpful for one’s heart health.
There appear to be other attributes of HDL that can be good. But researchers have also found that HDL’s role in health is complicated and ever-changing, with plenty to figure out.
Cholesterol has long been explained as the “good” versus the “bad.” A high level of the “good” kind has been tied to a lower risk of cardiovascular disease, while having lots of the “bad” kind — carried by low-density lipoprotein, or LDL, particles — has been linked to a higher risk.
One of the big reports to bestow HDL cholesterol with the label of “good” came out of the Framingham Heart Study, a government-led effort launched in 1948 to investigate risk factors for cardiovascular disease. In 1977, Framingham researchers reported an inverse relationship between HDL cholesterol and coronary disease risk in a group made up of white participants.
But later studies undercut the premise that high levels are automatically good for heart health. People with a genetic mutation that boosts their HDL cholesterol level , for example, do not have lower risk of heart attacks than people without the mutation ( SN: 5/18/12 ). And a class of drugs developed to increase HDL cholesterol did a great job upping numbers, but didn’t make a difference when it came to cardiovascular risk .
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A person’s HDL cholesterol level is just one part of the story, though. Commonly reported on blood tests, the level reflects the amount of cholesterol that HDL particles have on board. HDL carries cholesterol away from the arteries to the liver to be excreted. This helps keep cholesterol from building up in artery walls, which can eventually impede blood flow.
Recently, research on HDL has started looking beyond its cholesterol payload. “The big understanding over the last decade or so is that while you can measure the cholesterol, it doesn’t really reflect the actual functions that HDL is doing in the body,” says Anand Rohatgi, a cardiologist at the University of Texas Southwestern Medical Center in Dallas.
How well HDL removes cholesterol appears to matter. One measure of this job performance is HDL’s ability to receive cholesterol from a type of cell called a macrophage. In a U.S. study of close to 3,000 adults, 49 percent who were Black, the higher this capacity, the lower the incidence of heart attacks or strokes, Rohatgi and colleagues reported in the New England Journal of Medicine in 2014.
Ridding the body of cholesterol is just one of HDL’s many jobs. HDL also has anti-inflammatory and other protective effects that appear to guard against cardiovascular disease. But even these effects don’t always lead to a net good. In certain circumstances, HDL can become dysfunctional, such that its capacity to receive cholesterol is reduced , and it contributes to inflammation. The fact that HDL’s roles can change, depending on the context, has made studying HDL particles challenging, Rohatgi says.
How well HDL performs is still far from something that can be tested as part of a regular physical exam. It’s not clear “how to do it yet for the general public,” says Nathalie Pamir, a researcher who studies cardiology at the Oregon Health & Science University in Portland.
As researchers work toward a fuller understanding of HDL and how it might be better used as a clinical measure, the view of HDL cholesterol as uniformly “good” is still out there. And one’s HDL cholesterol level is still one entry in a widely used calculator that estimates cardiovascular risk. Pamir and her colleagues wanted to examine what high and low HDL cholesterol levels mean in a contemporary, diverse population.
In the new study, the team analyzed data from the REGARDS trial, designed to study potential regional and racial differences in death from stroke in the United States. The study included nearly 24,000 participants — of which 42 percent were Black — who did not start out with coronary heart disease. Over roughly 10 years, 664 out of 10,095 Black participants and 951 out of 13,806 white participants had a heart attack or died from one.
Increased levels of “bad” LDL cholesterol were tied to a higher risk of coronary heart disease, in line with past research, the team found. But for HDL cholesterol, high levels weren’t protective for anyone, and low levels were only predictive of higher risk in white people. That finding suggests it may be necessary to revisit how HDL cholesterol is used in the cardiovascular disease risk calculator, Pamir says.
Rather than just good, HDL cholesterol “is complicated,” she says. If a patient has high HDL cholesterol, a doctor “can say, ‘well, currently we don’t know what that means.’”
Although the study suggests that the impact of HDL cholesterol levels on disease risk may differ by race, it’s important to remember that race is a social construct, not a biological one, says Clyde Yancy, chief of cardiology at the Northwestern University Feinberg School of Medicine in Chicago.
Some of the risk factors for coronary heart disease, including high blood pressure and smoking, “are more prevalent in self-described Black Americans,” he says. And a community’s access to health care, nutritious food and opportunities for education and employment can influence those risk factors ( SN: 5/15/17 ). “There is something unique about place and the history of place which may predispose to the burden of hypertension, obesity, even diabetes,” Yancy says.
It will take more research to understand what’s behind the potential race-based difference that the study reports, Yancy says, and what it means in terms of HDL cholesterol levels and cardiovascular disease risk. But it remains the case that high levels of LDL cholesterol — which can accumulate in artery walls — are associated with an increased risk, he says. “The LDL cholesterol seems to be our most relevant barometer.”
For all that is known about what impacts cardiovascular disease risk, researchers still don’t have the full picture. The number of times that cardiologists see heart attacks in patients with normal cholesterol levels and normal blood pressure, Yancy says, suggests that, with current methods, “we’re not able to capture the entirety of the risk.”
N.A. Zakai et al . Race-dependent association of high-density lipoprotein cholesterol levels with incident coronary artery disease . Journal of the American College of Cardiology . Vol. 80, November 2022, p. 2104. doi: 10.1016/j.jacc.2022.09.027.
M. Ouimet, T.J. Barrett and E.A. Fisher. HDL and reverse cholesterol transport: basic mechanisms and their roles in vascular health and disease . Circulation Research . Vol. 124, May 10, 2019, p. 1505. doi: 10.1161/CIRCRESAHA.119.312617.
R.S. Rosenson et al . Dysfunctional HDL and atherosclerotic cardiovascular disease . Nature Reviews Cardiology . Vol. 13, January 2016, p. 48. doi: 10.1038/nrcardio.2015.124.
A Rohatgi et al. HDL cholesterol efflux capacity and incident cardiovascular events . New England Journal of Medicine . Vol. 371, December 18, 2014. doi: 10.1056/NEJMoa1409065
T. Gorden et al . High density lipoprotein as a protective factor against coronary heart disease . The American Journal of Medicine . Vol. 62, May 1, 1977, p. 707. doi: 10.1016/0002-9343(77)90874-9.
Aimee Cunningham is the biomedical writer. She has a master’s degree in science journalism from New York University.
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