People with High Ceramide Levels up to Four Times More Likely to Have Heart Attacks, Stroke

This is the tale of two lipids. One familiar, the other obscure. One a well-known risk factor for cardiovascular disease, the other just emerging as a distinct—perhaps even better—predictor of it.

The first of these waxy, fat-like substances is cholesterol, which in tandem with triglycerides (another type of fat found in the blood) has long been considered a strong indicator of heart disease and stroke. The other is ceramides, an important constituent of skin, that is used in many cosmetic products to moisten and rejuvenate aging epidermis. But in a new wrinkle, scientists have found that the effects of ceramides run more than skin deep.

In fact, scientists at University of Utah Health recently discovered that people with high blood levels of ceramides are at least three or four times as likely to have a stroke or heart attack than those with lower blood levels of this lipid. Using a newly developed test, the researchers also found evidence that ceramides—a class of lipids that is part of the sphingolipid family—are an independent indicator, or biomarker, of these conditions, predicting the presence of coronary artery disease (CAD) as well as or better than cholesterol.

However, the test, called Sphingolipid Inclusive CAD risk score, or SIC, will need to be validated and refined before it can be used clinically, according to the researchers. Their study appears in The Journal of Clinical Investigation.

“LDL cholesterol, the so-called ‘bad cholesterol,’ is a really imprecise measure of cardiovascular disease risk,” says Scott Summers, Ph.D., chair of U of U Health’s Department of Nutrition & Integrative Physiology at the College of Health. “Based on previous mouse studies, we strongly suspected that ceramides might be causative. This finding certainly adds to that body of evidence. It provides us with an opportunity to design new types of personalized medical interventions tailored to lower ceramides and other sphingolipids in individual patients that can potentially improve their health and decrease their risk of cardiovascular disorders.”

Like cholesterol, ceramides are sticky, greasy molecules that help maintain cell membranes and perform other critical life-sustaining tasks. In excessive amounts, both substances can wreak havoc on the cardiovascular system, promoting the accumulation of plaque in arterial walls. Yet, until recently, ceramides were much harder to detect because they are 1,000 times less abundant than cholesterol.

New clinical tests are available, but they can only detect a small fraction of the ceramides circulating in the bloodstream. And although previous research has found a strong correlation between circulating ceramide blood levels and coronary heart disease, the magnitude of that risk had rarely been quantified, nor had a broader panel of other sticky sphingolipid molecules been evaluated.

To address these concerns, Summers and his U of U Health colleagues Mary C. Playdon, Ph.D., assistant professor in the Department of Nutrition & Integrative Physiology, and doctoral student Annelise Poss used machine learning, a type of advanced statistical analysis that allows computers to train using the data to predict outcomes, to identify 32 ceramides or their precursors that are likely the most predictive biomarkers of coronary artery disease. Then, using their new SIC test for these lipids, they assessed blood samples from more than 460 people in Utah, ages 30 to 75, who were diagnosed with coronary artery disease between 1990 and 2000. They also tested blood from an additional 200 people of similar ages who were deemed healthy.

The scientists found that their new test, which relied on mass spectrometry to isolate tiny amounts of ceramides in the blood, was a better overall predictor of the presence of cardiovascular disease than currently used ceramide tests or LDL cholesterol measurements. In particular, ceramide concentrations were higher in those who had had a previous heart attack or who had insulin resistance or type 2 diabetes.

They also discovered that ceramides do not correlate strongly with triglycerides or other traditional measures of cardiovascular risk. The researchers say this finding suggests that ceramides and other lipids similar to them are a distinct and independent predictor of disease status and may in fact be a contributing factor to the development of heart disease and stroke.

To confirm and broaden the applicability of these results, which was based on blood drawn from Caucasian men and women in Utah, the researchers plan to validate the SIC score using blood samples collected up to 12 years before the onset of cardiovascular disease among multiracial populations throughout the United States, United Kingdom, China, and other countries. They will also analyze ceramide levels and their impact on cardiovascular disease in these groups.

In the meantime, Summers and Playdon are studying how diet, physical activity, and other lifestyle factors, many of which have changed significantly since the 1990s, could influence blood ceramide levels.

“Once we identify those factors, we can design intervention studies to test whether they can causally change ceramides,” says Playdon, an assistant professor in the nutrition and integrative physiology department. “These studies, in addition to replication in other populations, will serve as the basis for developing personalized guidance for modulating ceramides and further validating our sphingolipid panel as a CVD predictive biomarker.”