Advanced Lipid Testing: Enabling a More Accurate Assessment of Cardiovascular Disease Risk

Krauss, Ron M., MD
Senior Scientist and Director of Atherosclerosis Research
Children’s Hospital and Research Center Oakland
Oakland, CA
Adjunct Professor of Medicine
University of California San Francisco
Also by this Author 

Cardiovascular disease (CVD) is the leading cause of death for both men and women in the U.S. accounting for one in three (approximately 800,000) deaths each year.1 Strategies to reduce the burden of CVD focus on the three leading risk factors: hypertension, high cholesterol levels, and smoking. It is estimated that about half of U.S. adults aged 20 years or above have at least one of these risk factors.1

Approximately 71 million U.S. adults have elevated low-density-lipoprotein (LDL) cholesterol,a key factor in assessing CVD risk and the primary target of cholesterol-lowering therapy.2 Recent advances in lipid testing, however, indicate that a focus on LDL does not provide a complete picture of risk.

Dr. Ronald Krauss, Senior Scientist and Director of Atherosclerosis Research at Children’s Hospital Oakland Research Institute, cautions that physicians should not rely exclusively on LDL cholesterol for assessing or managing risk.He discusses how the direct measurement of lipoprotein particles, using ion mobility analysis, and an assessment of a patient’s overall lipoprotein particle profile, provides a basis for more accurate assessment of risk and monitoring of therapy.

Lipoprotein Sub-classes – A Marker for Risk

“Each class of lipoproteins has multiple components,” explains Dr. Krauss. “Work my colleagues and I performed a number of years ago established that LDL sub-classes differ in their relationship to risk. The small LDL particles, in particular, are much more strongly related to risk than the larger LDL particles.”3

This risk is associated with a cluster of other changes in the lipid profile including higher levels of triglyceride and VLDL and lower levels of HDL cholesterol – in particular of the larger HDL2, and specifically the HDL2b sub-class.2 “These three changes, and particularly that of the small LDL, which is the major component associated with heart disease, tend to occur together in many patients,” continues Dr. Krauss. “This profile, which we’ve called LDL pattern B, or atherogenic dyslipidemia, has been increasing in prevalence primarily because of the rising tide of obesity, diabetes and pre-diabetes, and this is now a major concern.”

Traditional Lipid Testing

The shortcoming of traditional lipid testing is that it only gives an approximation of levels of these important sub-classes, notes Dr. Krauss. “The smaller LDL in particular is relatively weakly correlated with LDL cholesterol. LDL cholesterol underestimates that measurement, in part because the small LDL actually have less cholesterol than other LDL particles. There is a greater likelihood of having higher small LDL particles when triglyceride levels are high and HDL levels are low because those tend to go together, but even that is a poor marker of levels of small LDL for use in practice. So it’s preferable, if you accept the importance of these profiles, to go deeper and measure the particles directly.”

Ion Mobility Testing – Enabling Direct Particle Measurement

The ion mobility test, which was pioneered by Dr. Krauss, is the fourth generation of testing developed to provide direct measurements of particles. “It’s really quite a significant breakthrough in technology,” he notes, “because all previous methods that have been in clinical use do not measure particle concentrations directly, so they may not accurately capture the absolute concentrations, which is really what’s important in assessing how to treat a patient.”

“Ion mobility measures levels of individual lipoprotein particles as a function of their size. You get a direct measurement of concentrations of all the lipoprotein fractions across the size spectrum from VLDL through HDL . This can then be used to assess the overall risk profile, but more importantly to monitor the effectiveness of treatment, especially when you’re trying to reduce the small LDL particles. The general consensus among specialists is that measuring lipoprotein particles in the blood is much more relevant in managing heart disease risk than using the standard lipid measurements.4 The ion mobility test is a way to enable that approach and to translate an assessment into terms you can measure and treat.”

Applying Ion Mobility Testing to Clinical Practice

Dr. Krauss believes that advanced lipid testing, using ion mobility, has application for patients of intermediate to high risk, who are considered candidates for drug treatment. “While there’s an increasing population now being treated with statins,” he observes, “we’re recognizing there’s considerable residual risk in patients on statins, despite the fact you get lowering of LDL cholesterol. Statins mainly lower the large LDL particles but have less effect on small and particularly very small LDL particles. Patients who have either high, or borderline high, triglycerides and low HDL cholesterol - a very common profile - and are being placed on statins, are particularly good candidates for evaluating and then monitoring levels of the small LDL particles. Those measurements provide a basis to help you decide whether additional treatments or more aggressive treatments are indicated.”

Statin Treatment and Residual Risk

Residual risk is an important issue stresses Dr. Krauss because of the growing prevalence of statin treatment. While there is more and more evidence for the benefit of statin therapy, that benefit is still limited. “The most successful trials for secondary prevention have demonstrated a risk reduction of 30% to 40%, and in one case 50%. This is impressive but it also means that 50%, 60% or 70% of the risk is not reversed by statins. So there are other factors involved, which we are working hard to identify. We know that the LDL pattern B profile - high levels of small LDL particles and low HDL2b - is part of that residual risk and what we’re trying to do is identify better ways of reducing that risk. But first you need to measure those particles.”

“This residual risk is particularly significant when considering statins for primary prevention in patients who just have an abnormal lipid profile or other risk factors,” continues Dr. Krauss. “In these cases you really have to consider the potential downsides of statins versus the benefits. We’re increasingly concerned about adverse effects with long-term statin use such as muscle problems and increased risk of diabetes. You have to be sure you don’t treat patients with statins who really don’t need them or for whom statins may not be the most appropriate treatment. People who have a high risk with the small LDL profile would frequently benefit from improved nutrition, particularly reduced intake of carbohydrates, as well as weight loss and exercise, before consideration of drug treatment.”


  1. Million Hearts: Strategies to Reduce the Prevalence of Leading Cardiovascular Disease Risk Factors — United States, 2011MMWR. September 16, 2011. Vol. 60. No. 36. 1248- 1252
  2. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). National Institutes of Health. NIH Publication No. 01-3670 May 2001
  3. Kiran Musunuru K, Orho-Melander M, Caulfield M et al. On Mobility Analysis Of Lipoprotein Subfractions Identifies Three Independent Axes Of Cardiovascular Risk Arterioscler Thromb Vasc Biol. 2009 November ; 29(11): 1975–1980. doi:10.1161/ATVBAHA. 109.190405.
  4. Clinical utility of inflammatory markers and advanced lipoprotein testing: Advice from an expert panel of lipid specialists. Journal of Clinical Lipidology (2011) 5, 338–367

Released on Tuesday, July 09, 2013