November 22, 2017
Cholesterol Testing: What\
Expert Q&A

Cholesterol Testing: What's on the Horizon

by Jeanine Barone  

Ronald M. Krauss, MD, is Senior Scientist and Dolores Jordan Endowed Chair at Children’s Hospital Oakland Research Institute, Professor of Medicine at UCSF, and Adjunct Professor of Nutritional Sciences at UC Berkeley. He is also a member of the editorial board of the UC Berkeley Wellness Letter and BerkeleyWellness.com, and coauthor of the Wellness Report Controlling Your Cholesterol. Among his research areas are blood cholesterol and other lipids (notably different subtypes of lipoproteins), and he has developed lipoprotein particle measurement tests that have been used by some clinical labs. He also focuses on the roles of genetics and diet in heart disease and on statins. We spoke with him about his thoughts on the future of screening measures for heart disease as well as about the latest thinking on the role of diet.

Beyond the measurement of LDL (“bad”) cholesterol, do you think that doctors will routinely measure the LDL particle size, density, and concentration of their patients in the near future? I know that is one of your special areas of interest.

Currently such testing is not considered routine and is not part of the guidelines for lipid screening. When people hear the term LDL [low-density lipoproteins], they think cholesterol, specifically “bad cholesterol”—and indeed LDL carries cholesterol in the bloodstream, where it can end up in arteries and contribute to atherosclerosis. But lipoproteins are a spectrum of complex particles and are much more than just the cholesterol they carry. Today routine blood tests measure only the amount of cholesterol in LDL, along with HDL [“good”] cholesterol, and triglycerides, which are important in determining coronary risk but aren’t everything. Some of the most important measurements, I think, involve lipoprotein particle concentrations, rather than particle size or density. Such LDL particle measurements can often help determine risk beyond the assessment provided by the standard tests. This is already being used extensively in the cardiology research community.

For most people, today’s standard lipid tests will capture a significant amount of their coronary risk. But for those who are borderline on standard risk assessment tools (such as the ACC/AHA Heart Risk Calculator) or have risk factors such as a family history of heart disease or lipid disorders, the particle measurements can add considerably to the predictive value of the tests to help determine if treatment, such as with statin drugs, is appropriate for them. Because more and more people are being considered for statins, I think there will be increased acceptance of these tests and they will become more widely used to help determine who is likely to benefit most from treatment.

[For more about LDL particle size and concentration, see Cholesterol: Size Matters.]

What predictions can you make for how lipids will be approached in, say, a decade?

There has been an explosion of interest in identifying biomarkers for cardiovascular disease, including subtypes of lipids that are now in the research domain. I think as time goes on, those tests will become more accessible to physicians and other clinicians. And I envision that there will be tests that mix various types of measurements of proteins and lipids and other markers that can be combined into a more comprehensive panel than is currently available. But exactly what those components are going to be is still anyone’s guess.

Certainly, some of the main candidates are lipoprotein particle measurements and also measurement of particular proteins found within LDL particles and other particles in the blood that are involved with atherosclerosis, such as remnant lipoprotein particles and intermediate-sized lipoprotein particles. Most physicians, let alone the general public, are not familiar with these factors. But the interpretation of these tests has not yet been standardized in a way that can be translated into clinical practice. That’s why this is still an active area of research for people like me to establish which of these measurements would provide the most value above and beyond the standard measurements. Some of these types of particles are potentially even more damaging to the arteries than LDL.

Which alternative marker seems to be the most important?

Lp(a) [lipoprotein(a), usually called “L-p-little-a”] is certainly a key particle that is structurally similar to LDL. About one-third of the population has elevated Lp(a) in the high-risk range, making it the most common genetic trait associated with heart disease. But the standard lipid screening tests do not measure Lp(a). It has been left aside, even though it’s a very powerful independent indicator of the risk of heart disease and stroke. In part, that’s because Lp(a) is very strongly determined by genetics so it’s out of the individual’s control—plus there haven’t been effective treatments for lowering it; (high-dose niacin lowers it only modestly. There have also been some issues regarding standardization of the measurement.

One reason to measure Lp(a) is not just to assess the risk in individuals but also in families. If we find a high level in someone who has had heart disease such as a heart attack or who has a strong family history of heart disease, it’s very likely that relatives will also have high Lp(a). It would be important to assess the risk in families to be able to counsel individuals who have high Lp(a) to be more careful tending to their other risk factors, trying to reduce their overall risk by diet, and perhaps taking cholesterol-lowering medications as a way of counteracting that increased risk. But until we have a treatment that can specifically lower Lp(a), it’s not going to be part of routine screening.

Since Lp(a) is an independent risk factor, do we have evidence that lowering it is beneficial?

We don’t at this point. It’s a catch-22. Even though there’s abundant evidence that Lp(a) is a strong risk factor, because we don’t have effective treatments to lower it, we can’t evaluate the benefits of lowering it.

New treatments are coming along, but are still very far down the pipeline. One drug that can consistently lower Lp(a) by over 80 percent is being clinically tested now. It’s pretty unique. If it can be shown that using it in people with high Lp(a) reduces the risk of cardiovascular disease, including stroke, this will take us a long way towards including Lp(a) as part of routine screening, particularly when there’s a strong family history indicating genetic risk.

But it’s conceivable that such treatments may lower Lp(a) but not be effective in reducing cardiovascular risk; there’s no guarantee that this will be of therapeutic benefit. However, the evidence is so strong that Lp(a) is a causative factor for heart disease and stroke that I think most of us in the field expect that lowering it will be beneficial.

What do you think about testing for C-reactive protein?

CRP is a controversial area. First, it’s quite clear that inflammation is a major component of cardiovascular disease. There’s no doubt that inflammatory processes can lead to blood clots and the clinical outcomes of heart disease and stroke. And CRP is a marker for inflammation. The challenge is that, while it is an indication of inflammation and has been associated with risk of cardiovascular disease, the evidence would suggest that CRP itself is not the cause of vascular problems. It’s a marker but is not directly involved in the process. So it has not yet been established that lowering CRP itself has therapeutic benefits. It’s a difficult situation in that if one is concerned about heart disease risk or has heart disease, and the standard test results are in the normal range, measuring CRP might provide a clue to this inflammatory component that might be excessively high in certain patients. What you do about it is not clear, because lowering CRP itself may not be the answer. What it may lead to is the prescription of statin drugs for people whose LDL levels may be normal but whose CRP is elevated, since statins have significant anti-inflammatory effects. The JUPITER study from 2008 suggested that statins can help reduce the risk of heart attacks in such people.

In my own clinical practice, there are already so many patients who are candidates for statins based on other criteria that the measurement of CRP doesn’t really help in making therapeutic decisions. And once such a patient is on a statin, we have already initiated the treatment that would be likely to have the greatest benefit at reducing inflammation. So while measuring CRP doesn’t often influence my treatment options, there are situations where it can help determine which people may be candidates for statins because of a high level of inflammation.

Is there evidence that raising low HDL (“good”) cholesterol is beneficial? There has been some research calling this into question.

The simple answer is no. So far, all the treatments that have been tested for raising HDL cholesterol have been found to be ineffective for reducing heart disease risk. It’s a little bit like the flip side of the CRP question. CRP is a risk factor for heart disease but lowering it may not necessarily be a way of reducing risk. For HDL, it’s the reverse, where low HDL is a strong risk factor for heart disease but there is no evidence yet that the available treatments that can raise HDL, including lifestyle and drugs, reduce risk by virtue of their effect on HDL. So there’s a disconnect here. Those treatments might have benefits but they may not be specifically related to the effects on HDL.

And again, this is a matter of measurement: What we’re talking about is HDL cholesterol. This is just one feature of HDL particles, which are even more complex than LDL, with many more components. So measuring HDL cholesterol turns out not to be the most meaningful way of assessing what may be important regarding the effect of HDL on heart disease risk. It’s a matter of digging deeper. On the horizon are tools and measures that could help tease out particular features or types of HDL particles that may be far more informative regarding heart disease and may actually be targets of treatment not reflected by the standard HDL cholesterol measurement.

I’m talking about the protein components or some combination of proteins in the HDL particle. There’s no question from animal studies and some human studies that there’s at least one protein in HDL—apolipoprotein A1 (apo A1)—that when increased therapeutically can reduce heart disease risk. If there were a way of effectively raising apo A1 in humans, that would potentially be an attractive therapeutic approach. That’s an example of what might be a more appropriate way of introducing HDL into the therapeutic picture—by identifying a protein like apo A1 or some other collection of proteins that may specify a therapeutic effect of HDL that could be targeted for treatment.

What are your thoughts about testing for HDL function as opposed to simply looking at HDL levels to assess risk?

We need to get at the specific forms of HDL that might be most important as targets for treatment. The function of those forms of HDL involve a number of processes that counteract plaque formation in artery walls, and one of them is the ability of HDL to remove cholesterol from plaque. HDL also has anti-inflammatory effects. There is an increasing interest in the potential of devising tests that could gauge those properties of HDL that are functionally relevant to heart disease. And they could involve specific proteins or particle types within HDL or functional HDL tests directly. The functional tests are available but are not in the clinical arena yet. The test, for example, would determine how effective an individual’s HDL particles may be in removing cholesterol from cells that would accumulate cholesterol in plaque. I don’t see these specialized tests moving to the clinic any time soon. But there may be ways we can pinpoint features of those functionally important HDL particles that could be measured clinically. My lab and many others are deeply involved in this endeavor.

Let’s talk about diet now. Are all dietary carbohydrates bad for lipids? Aren’t whole grains better than refined grains, for instance?

There’s a wide spectrum of carbohydrates that goes from very unprocessed grains, such as whole-kernel rye or brown rice, which have fairly minimal adverse effects on lipids, up to simple sugars, which have a much more dramatic effect on lipids than starches or whole-grain products. Having said that, we have actually done some studies showing that even whole-grain products that are the least processed can raise triglycerides [fats in the blood] and thus may still have an adverse effect on heart disease risk. So even if the effect may be blunted with the less processed carbohydrates compared with the more processed starches and sugars, there still may be adverse effects. For that reason, there has been a great deal of interest in diets in which total carbohydrate intake from all sources is reduced in an effort to improve the lipid profile that’s commonly associated with metabolic syndrome, a widespread public health problem that features obesity, insulin resistance, and pre-diabetes. All of these conditions tend to raise triglycerides, reduce HDL, and increase levels of LDL particles, specifically the small-sized LDL that is most associated with heart disease risk. And reducing total carbohydrates of all types can help improve this lipid profile. So even though there’s a range of effects from carbohydrates, certainly favoring the least processed dietary forms, there is a case to be made for lowering total carbohydrates in order to optimize lipids, particularly in patients with pre-diabetes or diabetes. For that reason, there are studies underway testing dramatic reductions in carbohydrate intake in patients with diabetes.

What are your favorite heart-healthy foods?

I guess my favorite recommendation is related to fish—fatty fish, in particular. The evidence is fairly strong from epidemiology and from some clinical studies that eating the equivalent of two portions a week of fatty fish, such as salmon and sardines, is a heart-healthy practice, though one has to be careful about sources because of contaminants, such as PCBs and mercury. Moderate intake of nuts such as walnuts and almonds has also been associated with reduced heart disease risk. In general, plant-derived foods are associated with heart health. Beyond that, frankly, there’s not a lot you can point to for specific cardiovascular benefits from particular foods.

Do you recommend or take any supplements that may affect blood lipids or heart health?

No, there’s really no evidence that dietary supplements have any beneficial effects on blood lipids with one exception, and that’s for people with very high triglyceride levels, who may be at risk not just for heart disease but also for pancreatic damage. For them, high doses of omega-3 fatty acids—found in fish oil—can lower triglyceride levels. There are prescription forms of high-dose omega-3s specifically designed for them, which are preferable to dietary supplements, since you can’t be sure what you are getting with supplements.

What do you recommend in general regarding ways to promote heart health?

I’m a big advocate of lifestyle. Many of us would benefit from more physical activity—ideally at least three hours of it a week. There are so many benefits of being physically and metabolically fit, not just for cardiovascular health, but also for overall health. Couple that with maintaining a healthy body weight as close as possible to the optimal range, which exercise may help you achieve. Also important is a diet that’s rich in vegetables and contains fish. Equally important is limiting foods with adverse effects, particularly added sugars and the trans fats found in partially hydrogenated oils, which are fortunately disappearing from the food supply.

The Mediterranean diet pattern, which has been linked to cardiovascular benefits in some clinical trials and observational studies, is attractive for many people partly because it includes high-fat foods, which had previously been discouraged. We’re no longer very concerned about the total amount of fat in the diet. We’re thinking more in terms of a healthy dietary pattern rather than specific components of the diet. Combine that with staying physically active and maintaining a healthy weight, and I think that’s a pretty good package. And there have been estimates that this kind of lifestyle could reduce the risk of heart disease by 80 percent. So if you could achieve these lifestyle goals, you would go a long way to reducing your risk of heart disease and the need for medications.

Also see 13 Tips for Preventing Heart Disease.