For years, we’ve heard that there are two primary types of cholesterol on a standard lipid panel that really matter for heart health. The first one is the low-density lipoproteins (LDL) or “bad cholesterol,” which you want to keep low. The other type is high-density lipoprotein (HDL), or “good cholesterol,” which you want to have as much of that as possible. Right? Well, recent research has suggested that the relationship between HDL cholesterol and cardiovascular disease is more complicated than previously believed. In fact, having high HDL may not necessarily mean that you’re at reduced risk of having a heart attack. Instead, it seems that how well your HDL functions is more important than how many HDL particles you have.
In this blog post, we’ll take a closer look at this crucial nuance in the HDL discussion, and describe how to keep yours working optimally.
What do we actually really mean by “cholesterol?”
Let’s get a better understanding of what cholesterol means when we discuss heart disease risk.
As you no doubt know, the human body is mostly water (around 60%). But fats do not mix with water, and instead cluster together with other similar molecules. Think of what happens when you pour olive oil and vinegar into a jar and let them sit undisturbed.
This presents an obvious problem: our bodies need to transport lipids to tissues via the bloodstream. Accordingly, fats are chaperoned through the body in structures called lipoproteins. Much of the time, when we talk about “cholesterol,” we’re actually referring to these structures and their interactions with the walls of the arteries.
There are a few different types.
LDL has a well-documented propensity to sneak through the top cell layer of blood vessel walls (the endothelium) under the right circumstances. Here, these particles often become lodged into the innermost layer of arteries (the intima).
When this happens, it elicits a response from the innate immune system sending white blood cells called macrophages to come gobble up the LDL.
Unfortunately, these cholesterol-loaded macrophages can themselves accumulate on the blood vessel walls. In fact, this is one of the first steps in the process of atherosclerosis. It is also the major reason why having high levels of LDL over the course of time associates with cardiovascular disease.
Luckily, there is an opposing force that can intervene here. HDL pulls excess cholesterol molecules away from the artery walls and curbs the accumulation of those fat-laden macrophages. This function is why HDL has been associated with reduced risk of cardiovascular mortality in population studies. Therefore, it makes intuitive sense that the more HDL you have, the better off you will be, right? Not so fast.
HDL – Not as awesome as we thought?
A large-scale epidemiological study published last month examined HDL cholesterol levels in more than 1.7 million military veterans. The researchers found, to their surprise, that both low levels and high levels of HDL were associated with premature mortality.
While this may have seemed strange and counterintuitive, several types of research over the past few years have raised questions about the actual nature of the relationship between high HDL and cardiovascular disease.
Genetic research has shown that individuals who are predisposed to have higher levels of 
LDL across the lifespan are at greater risk of having a heart attack, while those carrying genes related to lower levels seem protected. All that lines up with previous beliefs. However, the genetic relationship between different levels of HDL and heart disease risk is not nearly as strong. For instance, a 2012 study published in the Lancet found that people who carry gene variants that were exclusively associated with higher HDL levels did not have a lowered risk of heart attack.
Research modifying HDL amount also cast doubt on its presumed role. In a recent experiment, researchers induced advanced atherosclerosis in a group of mice. Then, the rodents had various genes inserted in order to modulate their blood lipids in different directions.
One gene transfer strategy dramatically lowered LDL cholesterol and other atherosclerosis-promoting lipoproteins by as much as 95%. Expectedly, atherosclerotic plaques and inflammation regressed. In contrast, a gene transfer that caused HDL levels to go way up failed to heal the atherosclerotic lesions.
In humans, raising HDL – like with high doses of niacin and certain drugs – also showed disappointing heart-health results. Studies testing the drug torcetrapib elicited a 72.1% rise in HDL levels in patients but this did not deter the progression of atherosclerosis, as was hoped. Infamously, using this specific drug actually associated with a marked increase in mortality.
Recent studies have cast doubt on whether having high levels of HDL is always protective. Click To TweetBut why?
Maybe it’s not about how much HDL you have – but whether your HDL is actually doing its job.
Quality vs quantity
The studies cited above were measuring the amount of HDL cholesterol in the circulatory system. But we actually need to look a lot more closely at what your HDL is doing – which can’t necessarily be inferred just from looking at blood levels.
As I alluded to earlier, HDL particles can do a number of good things. They can behave like tiny trash
collectors, extracting excess cholesterol molecules from cells in the lining of the blood vessels and carrying them to the liver to be recycled or excreted as needed.
This functional property of HDL is known as cholesterol efflux, and is arguably the most important role that HDL plays with respect to cardiovascular health. HDL efflux capacity has been shown to be inversely associated with coronary artery disease independent of HDL cholesterol levels.
HDL also suppresses inflammation and oxidation, both of which are directly relevant to the cardiovascular disease process.
When good cholesterol goes bad
HDL is a highly variable molecule. It can differ in size, shape, protein cargo, lipid content, etc. Although we don’t fully understand why or how it happens, HDL structure can change in response to environmental signals and with chronic diseases such as diabetes. Some of these changes can render the molecule “dysfunctional” at its job. These changes can actually occur without any discernible change to the HDL level in your blood work lab report.
Last year, scientists at the University of Pennsylvania examined HDL blood levels and the functionality of HDL particles in three groups of people (almost 1000, total), and found that the only measure that was associated with prevention of atherosclerosis was HDL function (not level).
They sorted the participants by cholesterol efflux capacity and found that subjects whose HDL ranked in the top third of cholesterol efflux capacity had 36% fewer heart attacks compared to those in the lowest third of HDL function.
When HDL is working poorly it may become, at best, a neutral to your health. Even more troubling, there is evidence to suggest that dysfunctional HDL may be actively harmful to health increasing oxidative damage and inflammatory activity, and ultimately, contributing to the atherosclerotic process. This would certainly explain why the relationship between plasma HDL levels and cardiovascular disease is not nearly as consistent as that of LDL cholesterol.
Tragically, people could be taking false comfort in having very high HDL levels – while that HDL may not be doing a whole lot to protect them.
HDL molecules may undergo chemical modifications that render them dysfunctional. Click To Tweet
How to make your HDL function better
While there currently is no commercially available tests that can identify HDL function, there are a few things that you can do right now to make HDL work better in your body.
Olive oil
We know people who adhere to a Mediterranean diet seem to be protected from 
cardiovascular disease relative to other populations. No component of that dietary pattern has a stronger association with heart health than olive oil. We often attribute these effects to the monounsaturated fatty acids in the oil, but data has emerged suggesting that the bioactive polyphenols found in the cold-pressed oil play a role. See our recent article for more information on this.
For instance, researchers randomly assigned a group of 47 healthy participants to consume olive oil that was either high (366 mg / kg) or low (2.7 mg / kg) in polyphenols over a 3-week period. It was a crossover design, so the participants were subjected to both conditions over the course of the study.
Neither of the olive oil interventions altered the amount of HDL, however, the high-polyphenol oil changed the form and function of the HDL particles. Metabolites from olive oil polyphenols bound to the lipoproteins making them bigger and less rigid, and therefore, making them more resistant to oxidation and better able to chaperone cholesterol from cells.
Tomatoes and tomato products
Tomatoes – including pastes and sauces – are also a fixture of the modern Mediterranean diet. Diets that are rich in such foods (7+ servings per 
week) have been associated with a 30% reduction in relative risk of cardiovascular disease. This is often attributed to a carotenoid called lycopene, which has potent antioxidant properties.
One potential mechanism through which lycopene may confer this protection may be through enhancing HDL functionality. In research out of the UK, 54 individuals were assigned into three different groups of lycopene intake: a control diet (<10 mg / week), a lycopene-rich diet (224-350 mg / week), and a lycopene supplement (70 mg per week).
Increasing lycopene intake – either through supplementation or via diet – resulted in measurable improvements in HDL function via changes in HDL-associated enzymes. This allowed HDL to function better at countering systemic inflammation and oxidation.
Exercise
It makes intuitive sense that what you eat can influence the state of blood lipids. But what about physical activity?
Researchers at UCLA looked at 90 young men and divided them into groups based on their established exercise habits. Among other things, they measured HDL cholesterol and used a novel biochemical test to measure how well the men’s HDL performed as an antioxidant.
The authors discovered that participants who weight-trained at least four days a week had better functioning HDL compared to their sedentary counterparts.
You might think – as I did – that this is probably because the men who worked out were less likely to be obese. We already know that excess body fat is associated with deleterious effects on lipids and other biomarkers.
Interestingly, though, this finding was independent of body mass. Both overweight and lean men who exercised exhibited better HDL function than the sedentary participants. The mechanisms underlying this finding is currently unclear, but what really matters is that there is something that happens via resistance training that makes HDL work better.
Key takeaways
- The human body transports fats through the blood via tiny biochemical assemblies called lipoproteins.
- High levels of LDL are associated with cardiovascular disease, due to the body’s response when LDL particles invade the walls of blood vessels.
- HDL is associated with less cardiovascular disease because they are able to transport cholesterol away from artery walls back to the liver. They also exhibit anti-inflammatory and antioxidant functions, which help to prevent and ameliorate atherosclerosis.
- Recent epidemiological and genetic studies have cast doubt on whether having high levels of HDL in circulation is necessarily protective against myocardial infarction. Additionally, drug trials that drastically elevate HDL do not appear to be effective at reducing risk of having a heart attack. The amount of HDL that you have is probably not the best predictor of cardiovascular risk – at least in isolation. LDL seems to be a more robust biomarker in this respect.
- HDL molecules are subject to chemical modifications that render them unable to perform their necessary functions. Consequently, HDL may not be universally protective – or may even be transformed into pro-inflammatory molecules. You can’t hang your hat on having high HDL cholesterol on a lipid panel.
- HDL function may be a better predictor of cardiovascular risk. However, there are currently no good ways to monitor HDL function at the consumer level.
- Components of the Mediterranean diet (lycopene from tomatoes, polyphenols from olive oil), as well as resistance training, seem to improve the functional properties of HDL.
References
Saleheen D, Scott R, Javad S, Zhao W, et al. Association of HDL cholesterol efflux capacity with incident coronary heart disease events: a prospective case-control study. 2015. Lancet Diabetes Endocrinol. 3(7):507-13.
Salazar J, Olivar LC, Ramos E, Chávez-Castillo M, et al. Dysfunctional High-Density Lipoprotein: An Innovative Target for Proteomics and Lipidomics. 2015. Cholesterol 2015: 296417.
