Straight from the heart: Mysterious lipids may predict cardiac problems better than cholesterol | Science –

A version of this story appeared in Science, Vol 379, Issue 6637.Download PDF

Stephanie Blendermann, 65, had good reason to worry about heart disease. Three of her sisters died in their 40s or early 50s from heart attacks, and her father needed surgery to bypass clogged arteries. She also suffered from an autoimmune disorder that results in chronic inflammation and boosts the odds of developing cardiovascular illnesses. “I have an interesting medical chart,” says Blendermann, a real estate agent in Prior Lake, Minnesota.

Yet Blendermann’s routine lab results weren’t alarming. At checkups, her low-density lipoprotein (LDL), or “bad,” cholesterol hovered around the 100 milligrams-per-deciliter cutoff for normal values, and her total cholesterol—the good and bad versions combined—remained in the recommended range. “I thought I was cruising along just fine,” she says.

But because Blendermann’s risk was unclear, in late 2021 her doctor decided to refer her to cardiologist Vlad Vasile at the Mayo Clinic. To pin down her susceptibility to atherosclerosis, Vasile prescribed a test for substances Blendermann had never heard of: lipids called ceramides. Long overlooked, they are emerging as powerful alternatives to standard markers of heart disease risk such as LDL cholesterol. Blendermann’s score was moderately high, suggesting that compared with a person with a low score, she was more than twice as likely to suffer a cardiovascular event such as a heart attack. “It woke us up big time,” she says. “The ceramides told me the bigger story.” She began to take cholesterol-lowering drugs and overhauled her diet and exercise regime.

Doctors and drug companies are also warming to the medical possibilities of ceramides. Blendermann is one of just a few thousand people in the United States to have undergone ceramide blood testing, which is only performed by the Mayo Clinic. But later this year, lab testing giant Quest Diagnostics will start to offer the analysis, potentially making it available to many more patients.

The first drugs specifically designed to lower ceramide levels are also on the horizon, with at least two companies hoping to begin clinical trials within the next year or so. And researchers are refining their picture of how these molecules, which account for less than 1% of the lipids in the body, exert such a powerful influence over our physiology. Ceramides are essential for a variety of cellular functions. But a stack of studies also implicates high levels of the molecules in heart disease and illnesses such as diabetes and fatty liver disease, suggesting they may cause havoc as well.

“There is overwhelming evidence that [ceramides] are major driving forces for metabolic dysfunction,” says physiologist Philipp Scherer of the University of Texas Southwestern Medical Center. That makes them valuable for assessing patients’ odds of developing some chronic illnesses—and “an excellent predictor of cardiovascular risk,” says Jeff Meeusen, co-director of cardiovascular laboratory medicine at the Mayo Clinic.

Still, the medical community has not embraced ceramides. Before that happens, cardiologists will have to accept an unfamiliar test and learn how to interpret the results alongside standard risk factors. And before patients start to receive ceramide-lowering drugs, developers will have to show that interfering with compounds fundamental to the body does more good than harm.

Until a little over 30 years ago, ceramides “were not on anyone’s radar screen,” says Yusuf Hannun, a lipidologist at Stony Brook University. The few researchers who did think about the molecules, which are found throughout the body, assumed they were metabolically inert. In 1993, Hannun and his colleagues performed one of the first studies that helped change that perception.

The researchers wanted to find out how a specific immune system molecule spurs malignant cells to commit suicide, protecting against cancer. They discovered the molecule acts through ceramides, suggesting the lipids are important for conveying messages within cells. Soon afterward, a new technique called liquid chromatography-mass spectrometry revolutionized the study of the lipids. The technique, which can sort complex molecular mixtures, revealed that cells carry numerous ceramide varieties—mammals boast more than 200 types—and scientists have been trying to tease out the molecules’ functions ever since.

Micrograph image of skin cells. In addition to cell membranes, Golgi complexes, and nuclei, there are groups of smaller bubble-like molecules.
The bubbles in this image of skin cells are rich in ceramides. The lipids help maintain the integrity of the skin’s outer layer—which is why ceramides are included in skin creams.Vshyukova/Science Source

One place the lipids are essential, says biochemist Ashley Cowart of Virginia Commonwealth University, is the skin, which “has a very diverse ceramide population.” There, they help maintain a solid protective layer—that’s why skin cream–makers load their products with synthetic ceramides or those derived from natural sources. In the skin and elsewhere in the body, cells incorporate different types of ceramides to finetune the fluidity of their outer membranes, which influences cellular functions such as movement, division, and communication. Ceramides also serve as raw materials for the synthesis of other lipids. In short, says lipid biochemist Tony Futerman of the Weizmann Institute of Science, “We can’t survive without ceramides.”

But as researchers have discovered, ceramides can also turn against us. They can infiltrate the lining of blood vessels and usher in LDL cholesterol particles, thus contributing to atherosclerosis. They can inhibit production of nitric oxide, a chemical messenger that relaxes artery walls and helps keep the vessels open. Some ceramides appear to promote insulin resistance, a defect in sugar metabolism characteristic of type 2 diabetes and other conditions. The molecules can also reduce energy production by mitochondria, the organelles that provide cells’ chemical fuel. And the cell suicide that ceramides can trigger, although protective against cancer, may damage healthy tissue in organs such as the heart.

Do-it-all molecules

Ceramides can raise the risk of disease—but when they are present at normal levels, they play critical roles in the body.

  • Seal outer layer of skin

  • Trigger suicide of cells

  • Control cell membrane fluidity

  • Stimulate internal cellular recycling

  • Provide substrates for synthesis of complex lipids

Why do ceramides sometimes go bad? Some are born that way. A particular ceramide’s character depends on the size of its acyl tail, a portion of the molecule that can contain from 12 to more than 26 carbons. “The length of the acyl chain has enormous importance in cell physiology and in cell pathophysiology,” Futerman says. In general, ceramide varieties with long tails are more damaging, and certain molecules with 16-, 18-, or 24-carbon tails may be the most dangerous, for reasons yet unknown.

Ceramides may also become deleterious when our bodies produce too much of them. We break down the fats we eat to yield fatty acids, some of which get shuttled into the pathway that produces ceramides. Our cells normally only manufacture small amounts of ceramides. When our diet contains too much fat, however, synthesis of the molecules booms. “The ceramide pathway is kind of a spillover pathway” for excess fatty acids, Scherer says.

The link to diet likely explains why ceramides surge in so many diet-related metabolic conditions. For instance, researchers using liquid chromatography-mass spectrometry have found elevated levels of specific ceramides in patients with obesity, type 2 diabetes, nonalcoholic fatty liver disease, and several types of cardiovascular conditions, including atherosclerosis, heart failure, and stroke. And rodent studies suggest ceramides may be more than just bystanders. Using chemical treatments or genetic manipulations to cut ceramide levels can protect the animals from many of these ailments.

Some researchers remain unconvinced. “Whether they are causative or a result—in my view, we don’t know,” Futerman says. But physiologist Scott Summers of the University of Utah, who has been studying ceramides for more than 20 years, is one of the researchers who accepts their health effects. “The data for us have been perfectly clear that these are important molecules.”

Researchers continue to dig deeper into the biology of ceramides, but they are also eyeing the lipids as potentially valuable biomarkers to gauge a patient’s heart disease risk. The traditional factors for assessing this risk include age, sex, whether the patient smokes or has diabetes, and lab measurements of lipids such as LDL cholesterol. However, these indicators don’t flag everyone who is in danger. In fact, about 15% of people who suffer heart attacks have no standard risk factors at all.

Ceramides may fill the gap. In one 2016 study, clinical pharmacologist Reijo Laaksonen of Zora Biosciences and Tampere University and colleagues analyzed cholesterol and ceramide levels in people with heart disease. Blood ceramides accurately forecast whether these people would die from heart attacks. For example, the abundance of one ceramide variety with a 16-carbon tail was 17% higher in patients who perished than in individuals who survived. In contrast, LDL cholesterol provided no insight—it was higher in the people who didn’t have heart attacks, the scientists reported. Laaksonen and his colleagues, as well as other research teams, have also found that ceramide levels reveal cardiovascular risk in the general population. Overall, studies on more than 100,000 people confirm the predictive power of ceramide testing, Laaksonen says. “It’s very fair to say the ceramide test is the best lipid-based risk marker for cardiovascular events.” Zora has licensed its ceramide scoring algorithms to the Mayo Clinic and Quest.

quotation mark

[Ceramides] are major driving forces for metabolic dysfunction.

  • Philipp Scherer
  • University of Texas Southwestern Medical Center

Meeusen says he and his Mayo Clinic colleagues are generally wary of new medical tests, but that the evidence for ceramide testing was compelling enough to start offering the assays to patients in 2016. The team was also swayed by research suggesting ceramides are involved in cardiovascular disease development. “Ceramides [are] more directly involved with atherosclerosis progression compared to cholesterol,” Meeusen says.

Despite those advantages, ceramide testing remains limited. Meeusen says the Mayo Clinic performs about 1000 of the analyses per month, mostly in-house requests. In comparison, the clinic performs several times that many standard lipid panels every day.

Other providers are beginning to offer ceramide testing as well, however. For example, most private clinics and about one-half of public hospitals in Finland do so, Laaksonen says. Quest’s imminent entry into the market will further increase availability.

Marc Penn, medical director for Quest’s Cardio Metabolic Endocrine Franchise, says the company decided to offer ceramide tests because they are essentially three tests in one. For most patients today, Penn says, doctors assemble a fragmentary picture of their risk for conditions such as heart disease and diabetes by performing separate tests for lipids, blood sugar, and inflammation. But measuring ceramides provides a comprehensive assessment of a patient’s risk for metabolic diseases because all three factors affect the levels, he says.

Nobody expects ceramide testing to usurp the standard lipid panel. A ceramide test is more complex to perform because it requires mass spectrometry, which is not available in most clinical labs. It is also about 10 times more expensive, running around $100 at the Mayo Clinic. Moreover, it remains to be seen how many practicing cardiologists will opt for the tests even once they’re easier to order.

A healthcare worker draws blood from an older patient’s arm with a syringe.
Blood drawn from patients isn’t routinely tested for ceramides, but that could change as research underscores the power of these lipids for revealing susceptibility to heart attacks and metabolic diseases.DMPhoto/

Neha Pagidipati, a preventive cardiologist at Duke Health, says she is open to the idea. “There is a place for additional measurements to understand who is at risk for cardiovascular disease.” Still, she says that although one of her patients asked about ceramide testing, she has never ordered it and remains unsure about its clinical value. “It needs to be clearer what I’d advise my patients to do with that information.”

Summers worries some recommendations based on ceramide results could be counterproductive. Researchers have noted that blood ceramide levels tend to fall after patients improve their diet, exercise more, or take cholesterol-lowering medications such as statins. Recommending exercise is probably safe, Summers says, but statins “might just be keeping [ceramides] in the liver, where they do a lot of their damage.” What’s missing are data from clinical trials in which researchers test whether interventions such as diet and lipid-lowering treatments not only reduce ceramide levels, but also translate into improved health.

In 2020, Laaksonen and colleagues launched the first trial that will try to address that omission. The researchers are identifying 2000 patients with heart disease who have high levels of ceramides and three other biomarkers of cardiovascular risk. One-half of the patients will enter an intensive program, receiving twice-yearly coaching sessions about diet and exercise and frequent advice from a smartphone app. They will also get tailored recommendations for blood sugar– and lipid-lowering drugs. The other half of the group will receive regular care from their physicians. The researchers plan to follow the participants for 3 years, measuring their rates of cardiovascular events, to determine whether the more aggressive approach provides disease protection in addition to reducing ceramide levels.

Although diet and exercise may reduce ceramide levels, some researchers have sought a more direct approach: drugs that disrupt ceramide synthesis or break down the molecules. So far, big pharmaceutical companies’ efforts to develop such drugs have faltered for various reasons. In the early 2010s, for instance, researchers at Eli Lilly and Company identified two compounds that block the enzyme SPT, which catalyzes the first step in ceramide synthesis. These molecules slashed ceramide levels in rodents by 60% to 80%. But they also caused the lining of the animals’ intestines to peel off, leading the company to kill further development.

Biotechs are now picking up where big pharma left off, Scherer says. The company that Summers co-founded in 2016, Centaurus Therapeutics, has crafted a molecule that inhibits DES1, the enzyme that catalyzes the final step in ceramide synthesis. Summers says blocking this enzyme is likely to be safer than targeting SPT, noting that his team deleted the gene for DES1 in rodents without serious side effects. Centaurus is now amassing the animal safety data the U.S. Food and Drug Administration (FDA) requires to greenlight a clinical trial, says Jeremy Blitzer, the company’s chief scientific officer. He wouldn’t speculate on a start date, but says, “We are on a short path to a first dose in humans.”

Another biotech, Aceragen, is probing a different compound that breaks down ceramides and plans to begin a clinical trial within a year. The company intends to test the drug for patients with a rare and often-fatal metabolic condition called Farber disease, which results in abnormally high ceramide levels.

Other researchers are pursuing different strategies for reducing ceramide concentrations, but their work is at an earlier stage. Cardiologist Christian Schulze of the University of Jena and colleagues are trying to replicate the effects of a drug known as myriocin, which cuts ceramide levels dramatically in mice, protecting them from heart failure, slowing atherosclerosis, and improving insulin sensitivity. The catch is that myriocin, which was isolated from a fungus, suppresses the immune system, which once made it a potential treatment for rejection of organ transplants. “The side effects are what it was developed for,” Schulze says. But immune suppression boosts vulnerability to infections.

Using the crystal structure of myriocin’s active site as a template, Schulze and his colleagues have developed several molecules that seem to trigger the same benefits without undermining immunity. They have tested these compounds in cells and plan to move on to rodent studies. Laaksonen and his colleagues have reached about the same stage with their work. They are aiming to reduce ceramide levels with short interfering RNAs, which diminish levels of specific proteins necessary for ceramide synthesis.

Whether these efforts will deliver practical anticeramide drugs remains to be seen. But patients like Blendermann are already benefiting from ceramides’ power as risk markers. After getting her test result, she began to exercise more and eat more green vegetables and leaner meats such as fish and chicken. “That was huge for me. I grew up in a meat and potatoes family,” she says. After 1 year, her ceramide score had plunged from eight to one, the second-lowest risk level. Her other lipids, including LDL cholesterol and total cholesterol, also improved. She credits the ceramide test with making her realize “I’ve got to get busy and get this right.”

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