For years, people concerned about their heart health have paid close attention to their personal stats, hoping for low levels of “bad” LDL cholesterol and high levels of “good” HDL cholesterol.
A pair of new studies published Wednesday in the New England Journal of Medicine offer some of the most persuasive evidence yet that a third indicator of heart health — a form of fat called triglycerides, which circulate in the bloodstream — may be just as important in determining heart health.
A massive genetic study led by a Boston cardiologist has identified a subset of people who carry rare mutations that cause them to have dramatically lower levels of triglycerides in their blood. Those people, in turn, were 40 percent less likely to have heart disease than people who didn’t have the mutation.
A European study published in tandem, including more than 75,000 people, confirmed that mutations in the same gene decreased triglyceride levels and the risk of heart disease to almost exactly the same extent as the Boston study.
The findings suggest that scientists should be looking for a way to mimic what the body does in those people with naturally low levels of triglycerides.
“Everyone’s been looking for what are the pathways — what are the key ways that people get heart attacks beyond LDL cholesterol,” said Dr. Sekar Kathiresan, director of preventive cardiology at Massachusetts General Hospital and an associate member of the Broad Institute who led the new study. “For 20 to 30 years, people have been thinking it’s HDL, and trying to raise HDL. This work suggests it’s actually the triglycerides that are important.”
It’s clear that lowering LDL cholesterol, which is targeted by drugs called statins, is an effective way to reduce heart disease risk.
But over the years, it has not been clear whether HDL and triglycerides are simply indicators of heart health or actual causes of heart disease. It has been an open question whether lowering or raising their levels will actively change people’s health -- in short, are these markers a thermometer or a thermostat?
The results of the new studies strongly confirm and extend a surprising insight first gained by using an older form of genome analysis to study a small population of Amish people. In that 2008 study, published in the journal Science, researchers gave participants a fatty, 1,500-calorie milkshake and then measured how their bodies responded over time.
They found that about 5 percent of Amish people who carried a mutation in the gene APOC3 did not have a characteristic spike in triglyceride after the milkshake. Researchers also found that those effects seemed to span a lifetime and, as a result, the arteries of those with the mutation had not hardened as much.
But because of the difficulty of gathering long-term data and the challenges of determining the cause of death among people who did not necessarily go to the hospital, the researchers could never conclusively finish the story and show that the genetic mutation definitely prevented heart disease.
“What’s exciting about this is it takes that to another place,” said Toni Pollin, an associate professor of medicine at the University of Maryland School of Medicine, who led the 2008 work. “Just as you’d expect from something that prevents coronary artery buildup, there is strong evidence that having [a gene mutation] reduces the risk of having a heart attack.”
Kathiresan and colleagues benefited from the revolution in genome technology, sequencing 18,666 genes in each of 3,734 people in their search for genes that appeared to be linked to triglycerides. Rare mutations in the APOC3 gene stood out.
Once they understood where to look, they searched for four mutations in that gene in more than 110,000 people. They found that people with any one of the mutations -- about 1 in 150 people -- were 40 percent less likely to have heart disease and had lower levels of triglycerides.
The APOC3 gene creates a protein that inhibits swift removal of triglycerides from the bloodstream. Researchers theorize that in people who are fortunate to have the mutation, the protein is greatly decreased, causing triglycerides to stay low.
In an earlier study on HDL, the Boston team found that genetic mutations that cause people to have high HDL cholesterol -- the “good” form -- appeared to have no effect on heart health. That result came around the same time that several high-profile clinical trials of HDL-raising drugs failed, suggesting that HDL was less important than widely thought.
Dr. Frank Sacks, a professor of cardiovascular disease prevention at the Harvard School of Public Health, said that while the new studies are important, they do not signal that people should forget about HDL.
For one thing, he said, HDL remains an excellent predictor of heart health. The exact mechanism for raising HDL may be crucial to developing drugs that are effective -- meaning two drugs that raise HDL through different means may have very different results. The drugs tried so far may not have raised it in the right way.
At least one company, Isis Pharmaceuticals in California, has a drug in development that lowers triglycerides by targeting the APOC3 protein.